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Saturday 19 May 2018

Dietary nutraceuticals as backbone for bone health

JournalsBooks Download PDF Advanced Outline Abstract Keywords 1. Introduction 2. Signaling pathways in osteoblasts 3. Signaling pathways in osteoclasts 4. Potential of natural agents against bone loss 5. Clinical trials 6. Conclusions References Figures (2) Fig. 1. Biochemical mechanism for bone loss/formation Fig. 2. Structure of Nutraceuticals linked with suppressing bone loss Tables (2) Table 1 Table 2 Elsevier Biotechnology Advances Available online 27 March 2018 In Press, Corrected ProofWhat are Corrected Proof articles? Biotechnology Advances Research review paper Author links open overlay panelManoj K.PandeyaSubash C.GuptabDeepkamalKareliacPatrick J.GilhooleyaMehdiShakibaeidBharat B.Aggarwale Department of Biomedical Sciences, Cooper Medical School of Rowan University, Camden, NJ, USA b Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi, India c Department of Pharmacology, Penn State College of Medicine, Hershey, PA, USA d Musculoskeletal Research Group and Tumour Biology, Chair of Vegetative Anatomy, Institute of Anatomy, Ludwig-Maximilian-University, Munich, Germany e Inflammation Research Center, San Diego, CA, USA https://doi.org/10.1016/j.biotechadv.2018.03.014 Get rights and content Abstract Bone loss or osteoporosis, is a slow-progressing disease that results from dysregulation of pro-inflammatory cytokines. The FDA has approved number of drugs for bone loss prevention, nonetheless all are expensive and have multiple side effects. The nutraceuticals identified from dietary agents such as butein, cardamonin, coronarin D curcumin, diosgenin, embelin, gambogic acid, genistein, plumbagin, quercetin, reseveratrol, zerumbone and more, can modulate cell signaling pathways and reverse/slow down osteoporosis. Most of these nutraceuticals are inexpensive; show no side effect while still possessing anti-inflammatory properties. This review provides various mechanisms of osteoporosis and how nutraceuticals can potentially prevent the bone loss. Keywords Phytoestrogens Bone loss Nutraceuticals Osteoclastogenesis Bone remodeling Osteoporosis Pro-inflammatory cytokines 1. Introduction Bone loss or osteoporosis is an aggravating factor for the precipitation of bone disease. Bone loss accounts for nearly 8.9 million fractures annually (Looker et al., 2017; Rachner et al., 2011). In the United States approximately 53 million people are at risk of developing bone loss (Looker et al., 2017). It is estimated that over 200 million women are suffering from osteoporosis (Looker et al., 2017), and by 2025 there will be three million fractures because of bone loss, which will amount to a staggering $25.3 billion annual economic cost. The characteristic feature of osteoporosis is a decrease in density, and strength of bone (Adler, 2014; Iniguez-Ariza and Clarke, 2015). The hallmark of healthy bone is the ‘honeycomb’ like structure seen on gross examination of specimen. However, an erosion of bone structure leads to an increase in pore diameter of the structural “honeycomb”, causing the bone to lose density and eventually strength (Adler, 2014; Iniguez-Ariza and Clarke, 2015). Factors including health problems, lifestyle, medical procedures, and medication can all contribute to bone loss. Additionally, rheumatoid arthritis (RA), lupus, inflammatory bowel disease (IBD), breast cancer, prostate cancer, leukemia, lymphoma, multiple myeloma, Parkinson’s disease, diabetes, hyperparathyroidism, Cushing’s syndrome, irregular periods, premature menopause, low levels of testosterone and estrogen in men, and chronic obstructive pulmonary disease (COPD) can all lead to osteoporosis (Adler, 2014; Clementini et al., 2014; Khanna et al., 2007; Kling et al., 2014). Furthermore, medical procedures such as weight loss surgery, gastrectomy, and gastrointestinal bypass surgery, and medicines including aromatase inhibitors, chemotherapeutic drugs, gonadotropin releasing hormone (GnRH), methotrexate, steroids (glucocorticoids), and thyroid hormones contribute to osteoporosis (Adler, 2014; Clementini et al., 2014; Khanna et al., 2007; Kling et al., 2014). Bone remodeling takes place continuously, (Iniguez-Ariza and Clarke, 2015; Kobayashi et al., 2003) and tightly maintained by both osteoblasts (OBs) the bone forming cells, and osteoclasts (OCs) the bone resorbing cells (Chambers, 2000; Iniguez-Ariza and Clarke, 2015; Rachner et al., 2011; Roodman, 1999). The transition of mesenchymal stem cells (MSCs) into differentiating OBs and monocyte/macrophage precursors into differentiating OCs are the main events in osteogenesis and bone remodeling (Boyle et al., 2003; Teitelbaum, 2000). A number of signaling pathways play critical role in controlling the commitment and differentiation of lineages by modulating the expression of genes (Iniguez-Ariza and Clarke, 2015; Khanna et al., 2007). The imbalance at any stage of differentiation will impair function of these two cell types results in bone diseases including, osteopetrosis, periodontal problems, and bone cancer metastases (Chen et al., 2010; Iniguez-Ariza and Clarke, 2015; Sethi and Aggarwal, 2007). Current treatment for bone loss includes; estrogens, estrogen receptor modulators, bis-phosphonates, and calcitonin. The US Food and Drug Administration (US FDA) has approved number of drugs, however, most of them are associated with severe side effects as reflected in Table 1, (Sethi and Aggarwal, 2007). Recently, antibodies against receptor activator of nuclear factor kappa-B ligand (RANKL), Denosumab, showed promising response by inhibiting bone resorption in postmenopausal women (Maricic, 2007), though Denosumab exhibited undesirable side effects (Table 1). Extensive studies on agents derived from natural sources demonstrated that natural agents are efficacious in the treatment of bone-related diseases. Importantly, these agents are safe and inexpensive (Fig. 1, Table 2). By utilizing various in vitro and in vivo models, number of studies demonstrated that agents derived from natural sources exhibit anti- osteoclastogenesis potential (Ichikawa et al., 2007; Sethi and Aggarwal, 2007). For example, 1'-acetoxychavicol acetate (ACA, from Alpina galangal, commonly called thai ginger) (Ichikawa et al., 2006a), acetyl-11-keto-beta-boswellic acid (AKBA, from Boswellia serrata, commonly known as salai guggul) (Takada et al., 2006), butein (from cashew) (Sung et al., 2011), curcumin and calebin A (from turmeric) (Bharti et al., 2004; Kim et al., 2012; Tyagi et al., 2016), cardamonin (from Alpinia katsumadai, commonly called cardamonin) (Sung et al., 2013), coronarin D (from Hedychium coronarium, commonly known white ginger lily) (Kunnumakkara et al., 2008), diosgenin (from fenugreek) (Shishodia and Aggarwal, 2006a, 2006b), embelin (from Embelia ribes, known as false black pepper) (Reuter et al., 2010), gambogic acid (from mangosteen) (Ma et al., 2015; Pandey et al., 2014), gossypin (from Hibiscus vitifolius, called as rose mallow) (Kunnumakkara et al., 2007), guggulsterone (from guggul tree Commiphora mukul) (Ichikawa and Aggarwal, 2006), honokiol (from Magnolia officinalis, common name hou po) (Ahn et al., 2006), isodeoxyelephantopin (from medicinal plant Elephantopus scaber Linn., commonly called elephant foot) (Ichikawa et al., 2006b), indole-3 carbinol (from Brassica species) (Takada et al., 2005), plumbagin (from Chitrak) (Sung et al., 2012), reseveratrol (from grapes) (Shakibaei et al., 2011; Zhao et al., 2014), simvastatin (Ahn et al., 2008), thiocolchicoside (from Gloriosa superba, common name flame lily) (Reuter et al., 2012), withanolides (from Ashwagandha) (Ichikawa et al., 2006c), zerumbone (from subtropical ginger) (Sung et al., 2009), zyflamend (polyherbal preparation) (Sandur et al., 2007) have been shown to inhibit osteoclastogenesis induced by RANKL (Fig. 1). This review summarizes the recent advancements in the understanding of the role of natural agents, particularly those derived from dietary resources, in bone remodeling. Table 1. FDA approved drugs used for bone loss and their side effects. Drug Chemical class Mechanism of action Side effects References Alendronate/risedronate/ibandronate/zoledronic acid Bisphosphonates Inhibits osteoclast GI toxicity, weight loss, bone pain, low calcium levels Gao et al. (2017), Grigg et al. (2017), Lai et al. (2005), Lange et al. (2017), Lindsay et al. (1999), Lu et al. (2016), Monda et al. (2017), Sharma and Pradeep (2012), Shimizu et al. (2017), Shin et al. (2017); Watanabe et al. (2016) Estrogen Sex steroid Inhibits osteoclast development Endometrial cancer, stroke Goetz et al. (2017), Khalid and Krum (2016), Sapir-Koren and Livshits (2017), Southmayd and De Souza (2017), Streicher et al. (2017), Wu et al. (2018) Raloxifene Estrogen mimic Inhibits osteoclast development Leg cramps, hot flashes Beekman et al. (2017)Das and Crockett (2013), Fernandez-Garcia et al. (2008), Gomes-Filho et al. (2015) Estren Estrogen derivative Inhibits osteoblast apoptosis Breast cancer Denosumab RANKL antibody Inhibits osteoclast development Nausea, diarrhea, cramps Cummings et al. (2018), Meier et al. (2017), Nakamura et al. (2017), Nakatsukasa et al. (2017) Calcitonin Peptide hormone Inhibits osteoclasts Nausea, skin redness, diarrhea Atbinici et al. (2015), Bandeira et al. (2016), Binkley et al. (2014), Liu et al. (2014), Mandema et al. (2014), Shohrati et al. (2015) Teriparatide Peptide Induces bone formation Pain, headache, diarrhea, hypercalcemia Canalis (2018), Dempster et al. (2018), Greenspan et al. (2018), Kaneko et al. (2017), Langdahl et al. (2017), Lu et al. (2017), Suzuki et al. (2018) Abaloparatide (TYMLOS) Peptide Induces bone formation, maintains BMD Headache, dizziness, nausea, hypercalcemia Reginster et al. (2017), Shirley (2017), Tella et al. (2017) Table 2. List of nutraceuticals connected with bone health. Natural agents Source Mechanism Models Reference Resveratrol Vitis vinifera (red grapes) ↓IL1, ↓IL-6, ↓(COX-2), ↓RANKL, ↓Wnt, ↓PPAR-γ, ↓TNF-α, ↓VEGF, ↓lamin, ↓NF-κB, ↑FOXO1, ↑HO-1, ↑Sirt1, ↑Runx2, ↑osterix, ↑p-ERK1/2, ↑AMPK, ↑ALP, ↑osteocalcin In vivo and in vitro Ke et al. (2015), Lee et al. (2017), Matsuda et al. (2018), Mobasheri and Shakibaei (2013), Tou (2015), Zhao et al. (2015) Curcumin Curcuma longa (turmeric) ↓NF-κB, ↓RANKL, ↓MMP-13, ↓CTX, ↓ROS levels, ↓PPAR-γ, ↓C/EBP alpha, ↓ERK, ↓JNK, ↓p38, ↓NFAT2, ↓NF-κB, ↑osteocalcin, ↑Wnt-signaling pathway, ↑Runx2, ↑Osterix, ↑Col1A1, ↑Osteonectin, ↑HO-1, ↑ALP In vitro and in vivo Bharti et al. (2004), Chen et al. (2016), Gu et al. (2012), Hou et al. (2016), Kim et al. (2011b), Oh et al. (2008), TenBroek et al. (2016), von Metzler et al. (2009)Wang et al. (2016), Xin et al. (2015) Quercetin Allium cepa (onions) ↓p-AKT, ↓RANKL, ↓PGE2, ↓TRAF6, ↓COX-2, ↓Bcl-2, ↓NF-κB, ↓Smad, ↓AP-1, ↑ER-α, ↑ALP, ↑ERK, ↑p38, ↑MAPK, ↑Osx, ↑Runx2, ↑BMP-2, ↑Col-1, ↑OPN, ↑OCN, ↑Bax, ↑Bcl-2 In vitro and in vivo Casado-Diaz et al. (2016), Derakhshanian et al. (2013), Gomez-Florit et al. (2015), Guo et al. (2012), Kim et al. (2006), Masuhara et al. (2016), Wang et al. (2014b), Wattel et al. (2004), Yamaguchi and Weitzmann (2011), Zhou and Lin (2014), Zhou et al. (2015) Withanolide (Withaferin A) Acnistus arborescens (hollow heart) ↓RANKL, ↓Smurf2, ↓NF-κB, ↑Runx2 In vitro and in vivo Khedgikar et al. (2013) Silibinin Silybum marianum (milk thistle) ↓ERK, ↓JNK, ↓p38, ↓NFATc1, ↓NF-κB, ↓OSCAR, ↓MMP-9, ↓TRAP, ↓PSCAR, ↓cathepsin-K, ↓AP-1, ↑Col-1, ↑CTGF, ↑BMP-2, ↑p-AKT In vitro Kavitha et al. (2014), Kim et al. (2009), Kim et al. (2012a), Ying et al. (2015) Rosmarinic acid Rosmarinus officinalis (rosemary) ↓NFATc1, ↓MMP-9, ↓TRAP, ↓cathepsin-K, ↓NF-κB In vitro Hsu et al. (2011), Omori et al. (2015) Lupeol Senegalia visco, Abronia villosa, Mangifera (Mango) ↓NF-κB, ↓NFATc1, ↓c-Fos In vitro and in vivo Im et al. (2016) Syringetin Lysimachia congestiflora (Creeping Jenny) ↓AKT, ↓mTOR, ↓RANKL In vitro Tsai et al. (2015) Oleanolic acid Phytolacca Americana, olive oil ↑osteocalcin, and ↑Runx2 In vivo Bian et al. (2012) Indole-3-carbinol cruciferous vegetables ↓iNOS, ↓IL-6, ↓NF- κB, ↓TNF-α, ↓IL-1, ↓NO, ↓PGE2 In vivo Dong et al. (2010), Yu et al. (2015) Obovatol Magnolia obovate (Japanese big leaf) ↓NF-κB, ↓JNK, ↓ERK, ↓c-Fos, ↓NFATc1 In vitro and in vivo Kim et al. (2014a) Gambogic acid Garcinia hanburyi (false mangosteen) ↓NF-κB, ↓CXCR4, ↓p-Akt, ↓p38, ↓Erk1/2, ↓IL-6 In vitro Pandey et al. (2014) Harpagoside Harpagophytum procumbens (wood spider) ↓ERK, ↓JNK, ↓Syk-Btk-PLCγ2-Ca(2+), ↓c-Fos, and ↓NFATc1 In vitro and in vivo Chung et al. (2017), Kim et al. (2015b) Wedelolactone Eclipta alba (false daisy) ↓PLCγ2, ↓GSK3β activity, ↓NFATc1, ↓NF- κB, ↓c-Src, ↓c-Fos, ↓Cathepsin-K, ↓NF- κB/c-Fos/NFATc1, ↑β-catenin, ↑Runx2, ↑Wnt/GSK3β/β-catenin In vitro and in vivo Liu et al. (2016a), Liu et al. (2016b) Celastrol Tripterygium wilfordii (thunder of god vine) ↓PGE2, ↓BMP-2, ↓Col 1, ↓Runx-2, ↓osteocalcin, ↓PGE-2, ↓AKT, ↓PI3K, ↓β-catenin, ↑GSK-3β In vitro Zou et al. (2016) Theaflavin-3,3′-digallate Camellia sinensis (tea shrub) ↓RANKL, ↓ERK, ↓c-Fos, ↓NFATc1, ↓TRAP, ↓CTSK, ↓Oscar In vitro and in vivo Hu et al. (2017) Zerumbone Zingiber zerumbet (bitter ginger) ↓NF- κB In vitro and in vivo Sung et al. (2009) Ursolic acid Ocimum sanctum (holy basil) ↓NFATc1, ↓NF- κB, ↓JNK, ↓TRAP, ↓CTSK, ↓MMP-9, ↓c-Fos, ↓NFAT In vitro and in vivo Jiang et al. (2015a)Xu et al. (2016) Piperine Piper nigrum (Black pepper) ↓p38 MAPK kinase, ↓c-Fos, ↓NFATc1, ↓p38/NFATc1/c-Fos In vitro Deepak et al. (2015b) Gingerol Zingiber officinale (Ginger) ↓IL-6, ↓NF- κB, ↑Collagen type I, ↑ALP, ↑ALP activity in vitro Fan et al. (2015) Embelin Ardisia japonica (Marlberry) ↓NF- κB In vitro Reuter et al. (2010) Andrographolide Andrographis paniculata (king of bitters) ↓calcitonin receptors, ↓cathepsin-K, ↓NF-κB, ↓p-TGF-β-activated kinase 1, ↓p-IκBα, ↓ERK/MAPK signaling pathway, ↓TRACP, ↓NFATc1, ↑Wnt/β-catenin, ↑ALP, ↑BSP, ↑OCN, ↑Runx2 In vitro and in vivo Jiang et al. (2015b), Ren and Zhou (2015)Wang et al. (2015)Zhai et al. (2014) Butein Toxicodendron vernicifluum (Chinese lacquer) ↓RANKL, ↓NF-κB, ↓PGE2, ↓iNOS, ↓TNF-α, ↓IL-6, ↓COL-2, ↓COX-9, ↓ADAMTS-4, ↓ADAMTS-5 In vitro and in vivo Sung et al. (2011), Zheng et al. (2017) Sulforaphane cruciferous vegetables ↓NF-κB, ↓OSCAR, ↓NDATc1, ↓cathepsin-K, ↓DC-STAMP, ↓OC-STAMP, ↑STAT1 In vitro (Kim et al. (2005b), Takagi et al. (2017) Silymarin Silybum marianum (milk thistle) ↓NF-κB, ↓JNK, ↓p38, ↓ERK, ↓NFATc1, ↓OSCAR, ↑collagen secretion, ↑osteocalcin, ↑BMP, ↑SMAD1/5/8, ↑Runx2, ↑BMP/SMAD/Runx2 In vitro and in vivo Kim et al. (2009), Kim et al. (2012b) Plumbagin Drosera and Nepenthes (pitcher plants) ↓NF-κB, ↓MAPK, ↓RANKL In vitro and in vivo Li et al. (2012), Sung et al. (2012) Honokiol Magnolia grandiflora (bull bay) ↓p-p38 MAPK, ↓ERK, ↓JNK, ↓NFATc1, ↓IL-6, ↓RANKL, ↓TNF-α, ↓NF-κB, ↑BMP-2, ↑Smad In vitro Choi (2011), Hasegawa et al. (2010), Yamaguchi et al. (2011) Fisetin Acacia greggiil, Acacia berlandieri, Quebracho colorado (Cat claw) ↓p38 MAPK, ↓c-Fos, ↓NFATc1, ↓DC-STAMP, ↓cathepsin-K, ↓ERK, ↓Akt, ↓JNK, ↓NF-κB, ↓TRAF6, ↓c-Src-2, ↓osteocalcin, ↑HO-1, ↑MKP-1, ↑Runx-1, ↑Col1A1 In vitro and in vivo Choi et al. (2012), Kim et al. (2014b), Leotoing et al. (2014), Leotoing et al. (2013), Sakai et al. (2013) Ellagic acid Juglans regia (Walnut) and many other fruits and vegetables ↓p38 MAPK In vitro Rantlha et al. (2017) Betulinic acid Betula pubescens (downy birch) ↓MMP-2, ↓MMP-9, ↓cathepsin-K In vitro and in vivo Park et al. (2014) Emodin Rheum emodi (Himalayan rhubarb) ↓RANKL, ↓PPARγ, ↓C/EBPα, ↑Runx2, ↑osterix, ↑COL1, ↑osteocalcin, ↑ALP In vitro and in vivo Chen et al. (2017), Kang et al. (2014), Yang et al. (2014) Caffeic acid Eucalyptus globulus (blue gum) ↓ERK1/2, ↓p38, ↓JNK, ↓AP-1, ↓c-Fos, ↓p-Akt.↓NFATc1, ↓TRAP, ↓cathepsin-K, ↓c-Src, ↑Runx2 In vitro and in vivo Duan et al. (2014), Tolba et al. (2017), Wu et al. (2012), Zawawi et al. (2015) Apigenin Petroselinum crispum (parsley), Thymus vulgaris (thyme) ↓ IL-6, ↓RANTES, ↓MCP-1, ↓MCP-3, ↓MCP-1, ↓RANKL, ↓c-Fms, ↑BMP-6, ↑Osteopontin, ↑Runx2, ↑p-JNK, ↑p-p38 In vitro Bandyopadhyay et al. (2006), Goto et al. (2015), Zhang et al. (2015) Luteolin Found in many cruciferous vegetables, fruits and herbs ↓ATF2, ↓p38 MAPK, ↓NFATc1, ↓TNF-α, ↓CTX, ↑Dnajb1, ↑Hsp90b1 In vitro Crasto et al. (2013), Kwon et al. (2016), Lee et al. (2009), Shin et al. (2012) Genistein Genista tinctoria (dyer’s broom) ↓osteocalcin, ↓TNF-α, ↓PPARγ, ↓adipsin, ↓NF-κB, ↑ALP, ↑ACP, ↑osteocalcin, ↑ALP, ↑TGFβ1, ↑Estrogen Receptor, ↑p38MAPK-Runx2, ↑NO/cGMP, ↑OPG, ↑SMAD5, ↑BMP2 In vitro and in vivo Dai et al. (2013), Heim et al. (2004), Li and Yu (2003), Ming et al. (2013), Zhang et al. (2016) Berberine Berberis vulgaris (barberry) ↓NF-κB, ↓Akt, ↑osteopontin, ↑osteocalcin, ↑Runx2, ↑p38 MAPK, ↑COX-2, ↑Wnt/β-catenin In vitro Hu et al. (2008), Lee et al. (2008)/Tao et al. (2016)Xu et al. (2010) Lycopene Solanum lycopersicum (tomato) ↓ALP, ↓IL-6, In vivo Ardawi et al. (2016), Iimura et al. (2014), Liang et al. (2012) Fig. 1 Download high-res image (896KB)Download full-size image Fig. 1. Biochemical mechanism for bone loss/formation. Chemical structure of common dietary agents. The main sources of the natural agents are indicated in the parenthesis. These agents can also be derived from other natural sources. 2. Signaling pathways in osteoblasts Signaling pathways are pivotal in the commitment and differentiation of OBs and OCs. A number of studies have identified the key players in the process of osteogenesis (Iniguez-Ariza and Clarke, 2015). 2.1. TGF-β-Smad signaling The TGF-β superfamily members bind and signal through dual type I and II transmembrane receptors, which contain serine/threonine kinase domains. Smad proteins play key role in transmitting signals from receptor to nucleus (Derynck and Zhang, 2003; Miyazono et al., 2000). One of the member of TGF-β superfamily, bone morphogenetic proteins (BMPs) is critical in osteogenesis (Chen et al., 2012; Wozney, 1992; Zhang et al., 2014). Existing in various isoforms, BMPs mediate variety of activities in skeleton tissues (Rahman et al., 2015). For example, BMP-2, -6, and -7, and -9 promotes bone formation (Kochanowska et al., 2007), while BMP-3 inhibits bone formation (Kokabu et al., 2012; Wang et al., 2014a). The BMP mediated signaling pathways are both Smad-dependent and - independent (Derynck and Zhang, 2003). Upon BMP stimulation transcription factor Runx2 and Smads physically interact and regulate the transcription of genes which facilitates differentiation of mesenchymal stem cells (MSCs) to osteoblast (Javed et al., 2008; Phimphilai et al., 2006). How BMP modulates the expression of Runx2 is not clear. Recent studies have shown that BMP does not directly regulate Runx2 expression in mesenchymal cells (Lee et al., 2003), but instead it modulates the expression of distal less homeobox 5 (DLX5) in osteoblasts (Lee et al., 2003; Ryoo et al., 1997), which induces Runx2 in osteo-progenitor cells (Lee et al., 2003). Additionally, BMP signaling also regulates genes critical in osteoblastic differentiation such as Hairy/enhancer of split related with YRPW motif 1 (Hey1; also called HesR1 and Herp2), Tcf7, ITF-2 (Tcf4), and interferon regulatory factor 8 (ICSBP) (Chen et al., 2012; Franceschi et al., 2003). The activation of MAPKs including ERK, JNK, and p38 is regulated by BMP-2 in osteoblastic cells. The BMP signaling induced MAPKs have distinct roles in regulation of osteocalcin expression (Aubin et al., 2004; Broege et al., 2013; Rahman et al., 2015). Furthermore, BMP activated p38 MAPK and Smads controls the MSCs differentiation by Runx2 (Aubin et al., 2004). Additionally, studies using mouse progenitor cells and chondrocytes have demonstrated that BMP-2 induces Osterix (Osx) expression (Matsubara et al., 2008). Several studies have demonstrated that BMP signaling is implicated in pathogenesis of variety of bone disorders such as bone metastasis, brachydactyly type A2, and osteoarthritis (Dathe et al., 2009; Katz et al., 2013; Shen et al., 2014). The group of Phimphilai et al. (2006) showed that suppression of BMP signaling disrupt the osteoblast differentiation (Phimphilai et al., 2006). Another studies of Tsuji et al. (2006) augmented the role of BMP-2 fracture repair (Tsuji et al., 2006). Overall, studies suggest that BMP-2 signaling is required for bone remodeling. Several studies have illustrated that natural agents induce the osteoblast specific differentiation through TGFβ-Smad signaling pathways. Along these lines it is shown that quercetin, celastrol, andrographolide, silymarin, and honokiol reduce the TGFβ-Smad signaling pathways thus induces the osteoblast specific differentiation (Casado-Diaz et al., 2016; Kim et al., 2006; Zou et al., 2016) (Choi, 2011; Kim et al., 2012a). 2.2. Fibroblast growth factor signaling The fibroblast growth factors (FGFs) are a family of secreted polypeptides. FGFs bind to FGF tyrosine kinase receptors (FGFRs) and regulate a number of biological events critical in endochondral and intramembranous ossification (Ornitz, 2005; Su et al., 2014). During embryonic development, FGFRs are expressed in the condensing mesenchyme, perichondrium and periosteum, which evolve in cartilage, osteoblasts, and cortical bone, respectively (Ornitz and Marie, 2015; Teven et al., 2014). Mutations in FGFRs are linked with pathological conditions in humans including cranio synostosis and chondrodysplasia syndromes (Johnson and Wilkie, 2011; Ko, 2016). However, the role of FGFR 1 signaling in OBs differentiation is contradictory, as it is also reported that this signaling suppresses differentiation of OBs. Probably, FGFR1 signaling does act in a stage-specific manner (Jacob et al., 2006). Nonetheless, it has been demonstrated that FGF activates the transcription factor Runx2 by MAPK pathways, and thus regulates bone formation (Park et al., 2010). Studies have shown that apigenin, berberine, curcumin, emodin, genistein, oleanolic acid, quercetin, resveratrol, silymarin, wedelolactone, and withanolide activate the transcription factor Runx2 through MAPK pathways, therefore regulate the bone formation (Goto et al., 2015; Gu et al., 2012; Khedgikar et al., 2013; Kim et al., 2012a; Lee et al., 2008; Zhang et al., 2015). 2.3. Wnt signaling pathway The Wnt/β-catenin pathway is particularly important for bone cell signaling (Baron and Kneissel, 2013; Wang et al., 2014c). Based on the various genetic models, it is unequivocally established that embryonic skeletal development and adult skeletal remodeling requires Wnt signaling (Wang et al., 2014c). The studies of Krishnan et al in 2006, first showed that Wnt signaling plays a critical role in bone formation. These studies demonstrated that mutation in LRP5 a co-receptor of Wnt is the main cause of alternation in bone mass (Krishnan et al., 2006). Eight missense mutations in LRP5 have been identified as causing high bone mass (Balemans et al., 2007; Niziolek et al., 2015), while several homozygous or heterozygous nonsense, frameshift, and missense mutations have been identified in osteoporosis-pseudo glioma patients leading to low bone density (Cheung et al., 2006; Laine et al., 2011). It has been suggested that canonical Wnt/β-catenin signaling increase bone mass through upregulating the development of OBs (Regard et al., 2012; Yavropoulou and Yovos, 2007). High levels of β-catenin signaling upregulate the expression of genes implicated in differentiation of OBs (Zhang et al., 2013). This evidence is derived from studies utilizing conditional knockout mouse model, where knock out of β-catenin causes ectopic chondrogenesis and abnormal osteoblast differentiation (Usami et al., 2016). Additional studies further strengthen the role of Wnt signaling in OBs induction, suppression of chondrocytic differentiation in early osteochondroprogenitors (Day et al., 2005; Glass II et al., 2005; Hill et al., 2005). It was shown that Wnt induced OBs stimulated the production of osteoprotegerin (OPG) which inhibit the OCs formation and induces the OBs differentiation (Day et al., 2005; Glass II et al., 2005; Hill et al., 2005). A recent study revealed that Wnt/β-catenin signaling allows activation of transcription factors important in osteoblastogenesis by suppressing CCAAT/enhancer binding protein alpha (C/EBPa) and peroxisome proliferator activated receptor gamma (PPARγ) (Kang et al., 2007). Knockout of C/EBPa or PPARγ expression in ST2 cells and mouse embryonic fibroblasts reduced adipogenic potential and caused spontaneous formation of osteoblasts (Song et al., 2012). Recently, a study using Col1a1- and an OCN-Cre genetic model demonstrated that β-catenin is required in postnatal bone homeostasis (Burgers and Williams, 2013). The non-canonical Wnt signaling is also reported to play a role in osteoblastogenesis (Okamoto et al., 2014). Tu et al. has shown that Wnt3a and Wnt7b each function in osteoblastogenesis through a protein kinase C delta (PKCδ) pathway (Tu et al., 2007). Among the natural agents that modulate the Wnt signaling pathways and regulate the osteoblast differentiations are curcumin, wedelolactone, celastrol, andrographolide, and berberine. These agents have been used to demonstrate their effect on osteoblastogenesis. Furthermore studies suggest that these agents induce osteoblast differentiation by modulating the Wnt/β-catenin signaling pathways (Chen et al., 2016; Jiang et al., 2015b; Liu et al., 2016b; Tao et al., 2016; Zou et al., 2016). 2.4. Ephrin signaling Ephrins mediates bidirectional signaling (Pasquale, 2008). There are two classes of ephrins, class A and B. The B class molecules include (ephrin B1 to B3) ligands for EphB tyrosine kinase receptors (B1 to B6), whereas the class A ephrins (A1 to A5) are ligands for glycosyl phosphatidylinositol (GPI) - anchored EphA receptors (A1 to A10) (Lisabeth et al., 2013). The axis of ephrin B/EphB receptors control patterning of the developing skeleton. The unregulated ephrin signaling is associated with cranio frontonasal syndrome (Edwards and Mundy, 2008; Wieland et al., 2004). The ephrin signaling is critical in communication between OCs and OBs (Zhao et al., 2006). This bidirectional communication is mediated by ephrinB2 ligand in OCs and EphB4, a tyrosine kinase receptor, in OBs (Zhao et al., 2006). Notably, reverse signaling from EphB4 in osteoblasts to ephrinB2 in OC progenitors lead to the inhibition of osteoclast differentiation (Takyar et al., 2013). EphB4 induces osteogenic regulatory factors, such as Dlx5, Osx, and Runx2, in calvarial osteoblasts, suggesting that EphB4 is upstream in the regulation of osteoblast differentiation (Zhao et al., 2006). As a whole, these studies establish the concept that ephrin-Eph signaling is important in maintaining bone homeostasis. A number of laboratories have shown that resveratrol, curcumin, quercetin, oleanolic acid, wedelocatone, celastrol, fisetin, emodin, genistein, and berberine induce osteoblast differentiation, thus preventing bone decay (Bian et al., 2012; Casado-Diaz et al., 2016; Dai et al., 2013; Lee et al., 2008; Leotoing et al., 2014; Liu et al., 2016a; Mobasheri and Shakibaei, 2013; Zhou and Lin, 2014; Zou et al., 2016). 2.5. Hedgehog signaling Studies have implicated the role of hedgehog (Hh) in skeletal signaling pathways (Yang et al., 2015). During skeletogenesis, Indian hedgehog (Ihh) and sonic hedgehog (Shh) are involved in patterning the axial, appendicular, and facial skeleton (Pan et al., 2013; St-Jacques et al., 1999). It has been illustrated that Ihh is expressed by prehypertrophic chondrocytes and coordinates growth and differentiation of chondrocytes (Chung et al., 2001). In humans, mutation in the Hh pathway leads to many skeletal deformities such as brachydactyly type A1, and Gorlin syndrome (Onodera et al., 2017). The effect of homozygous mutation of Ihh is thought to be associated primarily with a deregulation of chondrocyte homeostasis (Cai and Liu, 2016). Recent studies of Sreekumar V et al, showed that resveratrol induces osteogenic differentiation (Sreekumar et al., 2017), through the inhibition of hedgehog signaling. Few natural agents have been explored for their osteogenic potential through hedgehog signaling pathways. More studies are needed to confirm whether natural agents induce bone formation by modulating the Hh signaling. 2.6. Parathyroid hormone signaling Parathyroid hormone (PTH) can be targeted therapeutically to build bone (Morley et al., 2001). PTH has been used as an effective treatment for osteoporosis due to the fact that PTH exerts either a catabolic or anabolic effect, depending on the method of administration (Morley et al., 2001; Thomas, 2006). Recent insights into the structure of PTH, parathyroid hormone-related protein (PTHrP), and PTH/PTHrP receptor have further enhanced the understanding of its role in calcium and bone biology (Mundy and Edwards, 2008). Although it is well establish that PTH/PTHrP axis play a critical role in bone metabolism, further studies are needed in order to demonstrate whether agents derived from natural agents modulate PTH/PTHrP axis for bone metabolism. Additionally, it has been identified that phytoestrogens inhibits osteoporosis in menopausal group (Kotecha and Lockwood, 2005). In summation, these studies strongly suggest that natural agents have the potential to induce osteogenesis by modulating various signaling pathways integral in bone metabolism. However, more clinical trials and various models are needed to fully understand the potential of natural agents. 3. Signaling pathways in osteoclasts A recent study has shed light on the role of osteocytes in bone remodeling. A number of signaling pathways associated with osteoclastogenesis have been discovered. Thus the understanding of each step in the differentiation of OC is important in order to develop novel agents to prevent bone loss (Fig. 2). Fig. 2 Download high-res image (408KB)Download full-size image Fig. 2. Structure of Nutraceuticals linked with suppressing bone loss. Steps involved in the bone formation and bone resorption. Bone remodeling is a dynamic process, which is controlled by a variety of chemokines, growth factors, and transcription factors. The agents derived from natural resources either induce the bone formation or inhibit the process of bone resorption. MSCs, mesenchymal stem cells; FGFs, fibroblast growth factors; BMPs, bone morphogenetic proteins; TGF-β, transforming growth factor-β; FGFRs, fibroblast growth factor receptors; Runx-2, runt-related transcription factor 2; CFU-S, colony forming unit-spleen; M-CSF, macrophages colony stimulating factor; RANKL, receptor activator of nuclear factor kappa-B ligand. 3.1. RANKL signaling RANKL is an important member of TNF superfamily. RANKL is also known as TNF-related activation-induced cytokine (TRANCE), osteoprotegrin ligand (OPGL), or OC differentiation factor (ODF) (Boyce and Xing, 2007; Darnay et al., 1998). Mice deficient in RANK demonstrated profound osteopetrosis resulting from lack of OC differentiation, suggesting that RANK is required for OC differentiation (Dougall et al., 1999). The binding of extracellular signaling factor RANKL to RANK activates signaling cascades by recruiting the adapter protein TRAF6 which leads to multiple downstream events such as activation of MAPK (ERK, p38, and JNK), NF-κB, Src, and AKT (Armstrong et al., 2002; Kim and Kim, 2016). The RANKL induced signaling is negatively regulated by osteoprotegrin (OPG), which is encoded by TNF Receptor Superfamily Member 11b (TNFRSF 11b). The pre-OCs and OCs express OPG and competes with RANKL for binding to RANK. In humans autosomal recessive osteopetrosis involves mutations in the RANKL gene, which results in low numbers of osteoclasts (Pangrazio et al., 2012). The role of RANKL in rheumatoid arthritis has recently been elucidated at sites of pannus invasion into bone. Pettit et al. found that RANKL and RANK expressing OC precursor cells were confined to the erosion sites of pannus-bone (Pettit et al., 2006). OPG protein expression, on the other hand, was limited at sites of bone erosion. These results implicate RANKL in the pathogenesis of rheumatoid arthritis, and show that it provides a conducive environment that favors the activity and differentiation of OCs (Pettit et al., 2006). A variety of nutraceuticals have been shown to inhibit bone loss by modulating RANKL signaling, some of these are resveratrol, curcumin, quercetin, and plumbagin (Bharti et al., 2004; Sung et al., 2012; Wattel et al., 2004; Zhao et al., 2015). Using in vitro and animal models, studies have demonstrated that these natural agents inhibit osteoclastogenesis induced by RANKL, suggesting that natural agents have the potential to inhibit the bone loss. 3.2. NF-κB signaling The inactive dimers of NF-κB are sequestered in cytoplasm by binding with inhibitory protein IκB (Aggarwal, 2004; Hayden and Ghosh, 2008). The upstream kinase, IκB kinase (IKK), phosphorylates IκB, which induces the degradation of inhibitory protein (Aggarwal, 2004; Hayden and Ghosh, 2008). Once inhibitory protein is degraded, dimer released from complex and translocate to nucleus (Aggarwal, 2004; Karin and Lin, 2002). Patients suffering from X-linked osteopetrosis, lymphedema, anhidrotic ectodermal dysplasia, harbor a X420W point mutation in IKKγ, thus constitutively activated NF-κB, leads to severe osteopetrosis (Boyce et al., 2015; Roux et al., 2002; Walsh and Choi, 2014). Several studies using genetically engineered mouse models suggest that NF-κB pathway is key in RANKL induced osteoclast development and function. RANKL can induce both classical and alternative NF-κB activation in OCs and their precursors (Novack, 2011). Deletion of IKK2 (IKK2−/−) in transgenic mice caused defective osteoclastogenesis in OC precursors in response to RANKL, TNF-α, or IL-1β, which resulted in osteopetrosis (excessive bone formation) and resistance to inflammatory-associated bone loss in vivo (Ruocco et al., 2005). Osteopetrosis and impaired osteoclastogenesis were reported in the transgenic mice with p50/p52 deletion, and the phenotypes were rescued by bone marrow cell transplantation (Franzoso et al., 1997; Iotsova et al., 1997). The pro-inflammatory cytokines, IL-1β and TNF-α, induced osteoclastogenesis via direct activation of OC precursor cells, or indirect induction of RANKL secretion in bone marrow stromal cells (McLean, 2009; Schett, 2011). Nevertheless, the dependence of RANKL/RANK signaling in the OC activation process is still a highly debated topic. Kobayashi et al. first reported that murine bone marrow myeloid cells differentiated into TRAP+ OCs in the presence of M-CSF and TNF-α (Kobayashi et al., 2000). The bone-resorption ability in OCs and RANKL secretion in OBs stimulated by TNF-α was dependent on IL-1β (Kobayashi et al., 2000; Wei et al., 2005; Zwerina et al., 2007). Antibodies against TNF-α receptors but not RANKL were observed to inhibit this process, suggesting that the TNF-α-mediated OC activation is independent of RANKL/RANK signaling. Inhibition of RANKL by OPG at an earlier stage of OC differentiation (exposed to M-CSF alone) augmented TNF-α-mediated OC activation. Interestingly, bone marrow myeloid cells deficient in RANK can differentiate into OCs by TNF-α stimulation; this demonstrated the existence of RANKL/RANK-independent pathway of OC activation (Kim et al., 2005a). It is clear from afore mentioned studies that agents inhibiting NF-κB signaling would have beneficial effects on bone loss. Several nutraceuticals have been identified for example resveratrol, curcumin, quercetin, withanolide, silibinin, rosemarinic acid, obovatol, gambogic acid, wedelolactone, zerumbone, ursolic acid, embelin, butein, silymarin, plumbagin, honokiol, fisetin, and berberine modulate NF-κB signaling pathways thus control bone loss (Bharti et al., 2004; Hu et al., 2008; Jiang et al., 2015a; Kavitha et al., 2014; Khedgikar et al., 2013; Kim et al., 2014a; Kim et al., 2009; Leotoing et al., 2013; Liu et al., 2016b; Mobasheri and Shakibaei, 2013; Omori et al., 2015; Pandey et al., 2014; Reuter et al., 2010; Sung et al., 2011; Sung et al., 2009; Sung et al., 2012; Wattel et al., 2004; Yamaguchi et al., 2011). 3.3. Macrophage-colony stimulating factor The macrophage-colony stimulating factor (M-CSF), facilitates the commitment of MSCs to pre-OCs (Qiao et al., 1997; Udagawa et al., 1990), which is one of the main events in OCs differentiation. Studies have established that proliferation, differentiation, and survival of hematopoietic cells are all dependent on M-CSF signaling (Feng and Teitelbaum, 2013). Furthermore, M-CSF also regulates cytoskeletal changes (Boyle et al., 2003). The studies demonstrated that M-CSF deficient osteopetrotic (op/op) mutant mouse exhibit osteopetrotic phenotype, which strongly suggests that M-CSF is required for OC differentiation (Takatsuka et al., 1998; Umeda et al., 1996), because these deficiencies can be reversed by injecting M-CSF (Umeda et al., 1996). How M-CSF stimulates the commitment of MSCs to pre-OCs is still poorly understood, nonetheless it is reported that binding of M-CSF to its receptor c-Fms recruits variety of adapter proteins and kinase which further activates downstream signaling pathways. Similarly, the studies of Cappellen et al. illustrate that M-CSF induces RANK, TRAF2A, PI3-kinase, and MEKK3 which are critical in regulation of OCs differentiation (Cappellen et al., 2002). Moreover, M-CSF stimulates the survival of OCs precursors by activation of survival protein Bcl-xL (Boyce, 2013). As discussed above, the role of M-CSF on the osteoclastogenesis is not fully understood. Nonetheless, studies on natural agents suggest that quercetin (Casado-Diaz et al., 2016), syringetin (Tsai et al., 2015), caffeic acid (Wu et al., 2012) may inhibit the commitment of MSCs to pre-OCs by modulating PI3K kinase pathways. However, more studies are required to fully delineate the mechanism. 3.4. Src Src belongs to the non-receptor tyrosine kinase (NRTK) family (Boggon and Eck, 2004). The evidence suggests that Src plays critical role in osteoclastogenesis was demonstrated in genetically engineered mouse models. These mice lack functional Src and produce an osteopetrotic skeletal phenotype (Marzia et al., 2000). The absence of Src affects the bone-resorbing activity of mature OCs, but does not affect OC formation (Miyazaki et al., 2004). A key function of Src in OCs is to promote the rapid assembly and disassembly of the podosomes, the specialized integrin-based attachment structures of OCs and other highly motile cells (Destaing et al., 2008). All together, these studies have demonstrated that Src is essential for bone resorption. It has been demonstrated that wedellactone (Liu et al., 2016a), and fisetin (Choi et al., 2012) inhibit bone loss through the inhibition of Src. 4. Potential of natural agents against bone loss It is evident from the section above that a balance of OBs and OCs is necessary in order to maintain healthy bone. Thus, agents that can modulate the expression of key players involved in bone metabolism would be of great interest. As noted in Table 2, agents derived from natural resources regulate the expression of key players. Some of these natural agents, which have been tested in the context of bone loss, are discussed below. The chemical structures of these agents are shown in Fig. 1. 4.1. Curcumin (Curcuma longa) Curcumin is a main coloring component of turmeric (Curcuma longa). Traditionally, curcumin has been used as a spice in Indian subcontinent for many years (Aggarwal et al., 2006). The ancient use of this agent is described in Ayurveda, which is an Indian system of medicine. Several bodies of evidence using in vitro and in vivo models suggest that curcumin may be used against bone loss. Many have demonstrated that curcumin downregulates the activation of NF-κB, Wnt/β-catenin, RANKL, and TNF-α all are linked with bone loss (Kim et al., 2012; Singh and Aggarwal, 1995; von Metzler et al., 2009). The cytokines RANKL, M-CSF, and recently discovered high mobility group box 1 (HMGB1), a chromatin protein, play a critical role in OCs differentiation. Curcumin can inhibit the osteoclastogenesis by inhibiting HMGB1 release in a P38-MAPK dependent mechanism (Sakai et al., 2012). The work of our group demonstrated that curcumin inhibits RANKL induced osteoclastogenesis (Bharti et al., 2004). Furthermore, we also demonstrated that turmeric possess the potential to inhibit bone loss (Kim et al., 2012). Another study by von Metzler et al demonstrated that curcumin diminishes human osteoclastogenesis by inhibition of the signalosome-associated IκB kinase (von Metzler et al., 2009). Several studies from other laboratories have illustrated that curcumin protects against ovariectomy-induced bone loss (Kim et al., 2011b). The curcumin analog UBS109 prevents breast cancer induced bone loss (Yamaguchi et al., 2015). Studies by Wang et al., 2016, demonstrated that curcumin enhances the osteoblast differentiation of human adipose-derived MSCs by inhibiting Wnt/β-catenin signaling, suggesting curcumin may control the bone metabolism (Wang et al., 2016). 4.2. Resveratrol (Vitis vinifera) Resveratrol was first isolated from white hellebore roots (Veratrum grandiflorum O. Loes). Since then, resveratrol has been isolated from various plants including grapes, berries, and peanuts. The work from our laboratory has shown that resveratrol suppresses the NF-κB activation (Manna et al., 2000), a key player of bone loss. Recent studies indicate that this stilbene may play a role in the prevention and treatment of bone loss; for example, Zaianbadi et al showed that by inducing SIRT1, resveratrol regulates RUNX2 thus inducing the differentiation of OBs (Zainabadi et al., 2017). Another study demonstrated that analogs of resveratrol inhibit osteoclasotogenesis by deacetylating FoxOs in a murine model (Kim et al., 2015a). Similarly, using in vivo model, Lee et al showed that resveratrol inhibits methotrexate induced bone loss (Lee et al., 2017). Various animal models further demonstrate that resveratrol supplementation retards bone loss. Nonetheless, additional clinical trials are needed to fully comprehend the utility of this stilbene against bone loss (Dosier et al., 2012; Tou, 2015; Zhao et al., 2015). 4.3. Quercetin (Allium cepa) Quercetin is a flavonoid found in a variety of fruits and vegetables, and has an especially high concentration in onions. The name quercetin was used in 1857, when this flavonoid was isolated from oak tree (Quercus sp.). This flavonoid is believed to either activate osteoblast or inhibit the OC differentiation, thus regulating bone metabolism (Casado-Diaz et al., 2016). Quercetin induces OB differentiation by activating Smad (Yamaguchi and Weitzmann, 2011), and P38 MAPK (Zhou et al., 2015), and inhibiting WNT/β-Catenin pathways (Casado-Diaz et al., 2016). Furthermore, studies have demonstrated that quercetin inhibit RANKL induced osteoclastogenesis through inhibition of NF-κB activation (Yamaguchi and Weitzmann, 2011). The studies of Tsuji et al have demonstrated that supplementation of quercetin can inhibit bone loss in an ovariectomy mouse model (Tsuji et al., 2009). All these studies suggest that this flavonoid has great potential to be used as a bone health supplement. However, further clinical studies are needed to fully elucidate the utility of this natural agent. 4.4. Genistein (Glycine max) Genistein an isoflavone, was first isolated in 1899 from the dyer's broom, Genista tinctoria. Although found mostly in soy, isoflavone is also found in a wide variety of foods. A number of in vitro and in vivo studies have demonstrated that genistein has the potential to prevent bone loss (An et al., 2016; King et al., 2015; Zhang et al., 2016). Along the same line of thinking, several mechanisms have been proposed. For example, isoflavone was found to induce osteoblast differentiation by upregulating PPARγ (Zhang et al., 2016), BMP2, Wnt/β-catenin (Kushwaha et al., 2014), Smad5, Runx2 (Dai et al., 2013), oestrogen and oestrogen receptors (ERs) (Liao et al., 2014). Isoflavone also inhibit osteoclastogenesis by either inhibiting number of transcription factors, which are critical in bone loss such as NF-κB, AP-1 (Liao et al., 2014) or bone loss associated cytokines such as IGF-1 and TGFβ (Joo et al., 2004). These studies clearly demonstrate that dietary supplementation of soy product can be beneficial in the prevention of bone loss. 4.5. Other natural agents Several other natural compounds have been found to exhibit anti-osteoporosis potential. Studies from our laboratory and by others have shown that 1'-acetoxychavicol acetate (ACA) (Ichikawa et al., 2006a), acetyl-11-keto-beta-boswellic acid (AKBA) (Takada et al., 2006), apigenin (Goto et al., 2015), betullinic acid (Park et al., 2014), berberine (Wei et al., 2009), butein (Sung et al., 2011), capsaicin (Kobayashi et al., 2012), catechin gallate (Shen et al., 2009), caffeic acid (Zawawi et al., 2015), curcumin and calebin A (Bharti et al., 2004; Kim et al., 2012; Tyagi et al., 2016), coronarin D (Kunnumakkara et al., 2008), diosgenin (Shishodia and Aggarwal, 2006a, 2006b), embelin (Reuter et al., 2010), emodin (Chen et al., 2017), eugenol (Deepak et al., 2015a), fisetin (Leotoing et al., 2014), gambogic acid (Ma et al., 2015; Pandey et al., 2014), gossypin (Kunnumakkara et al., 2007), guggulsterone (Ichikawa and Aggarwal, 2006), γ-tocotrienol (Deng et al., 2014), harpagoside (Kim et al., 2015b), honokiol (Ahn et al., 2006), isodeoxyelephantopin (Ichikawa et al., 2006b), luteolin (Kim et al., 2011a), lycopene (Iimura et al., 2015), obovatol (Kim et al., 2014a), oleanolic acid (Zhao et al., 2011), plumbagin (Sung et al., 2012), reseveratrol (Shakibaei et al., 2011; Zhao et al., 2014), rosmarinic acid (Lee et al., 2015), silymarin (Mohd Fozi et al., 2013), thiocolchicoside (Reuter et al., 2012), wedelolactone (Liu et al., 2016b), withanolides (Ichikawa et al., 2006c), zerumbone (Sung et al., 2009), and zyflamend (Sandur et al., 2007) all have tremendous potentials to inhibit osteoclastogenesis. 5. Clinical trials Clinical trials have been conducted for several natural products, as well as formulations containing combinations of these agents. One of the most widely studied nutraceutical curcumin, has demonstrated potential for a number of bone related problems such as arthritis, rheumatoid arthritis (RA), and osteoarthritis. In a recent study, curcumin was found to inhibit osteoclastogenesis in PBMCs derived from rheumatoid arthritis patients (Shang et al., 2016). The effectiveness of a surface controlled water dispersible form of curcumin named Theracurmin was also assessed among the patients suffering from knee osteoarthritis (Nakagawa et al., 2014). A randomized, double blind, placebo-controlled prospective study was performed in fifty patients. Theracurmin containing 180 mg/day of curcumin was administered orally every day for 8 weeks and knee symptoms were evaluated at 0, 2, 4, 6, and 8 weeks. Additionally, blood analysis was performed to monitor for adverse effects. The study clearly demonstrated that after 8 weeks of treatment knee osteoarthritis was effective without any adverse side effects (Nakagawa et al., 2014). Studies of Riva et al., 2017a, 2017b further establish that curcumin-based supplementation in combination of healthy lifestyle may be beneficial in osteopenia (low bone density). In this study oral formulation of turmeric was used in patients (n=57) suffering from osteopenia (Riva et al., 2017a, 2017b). Several other clinical trials further suggest that curcumin has a tremendous potential for the prevention of bone loss, importantly curcumin exhibits no side effects (Belcaro et al., 2010; Chandran and Goel, 2012; Chin, 2016; Daily et al., 2016; Henrotin et al., 2014; Panahi et al., 2014; Rahimnia et al., 2015). A randomized double-blind placebo controlled study was performed on genistein to evaluate its effect on bone loss in postmenopausal women compared to hormone-replacement therapy (HRT) (Morabito et al., 2002). Studies by Cotter A., et al confirmed that genistein reduces bone resorption and increases bone formation in postmenopausal women (Cotter and Cashman, 2003). Another randomized, placebo-controlled, double-blind pilot study by Lappe J et al further confirmed that genistein in combination with polyunsaturated fatty acids, and vitamins D3 and K1 inhibits the bone loss in postmenopausal women. The paramount importance of these studies was derived from the fact that no toxicities were observed (Lappe et al., 2013). Though the use of various phytoestrogens derived from various sources inducing soya (genistein), red cloves, dietary products have beneficial effects on bone loss, however controversial results also been observed (Abdi et al., 2016). Thus more detailed studies and clinical trial are needed in order to gain more insight into the advantages of natural non-toxic agents (Abdi et al., 2016). Studies by Lamb J et al demonstrated that the anti-inflammatory agent berberine, a combination of hop rho iso-alpha acids, vitamin D₃, and vitamin K inhibits the bone loss in postmenopausal women with metabolic syndrome (Lamb et al., 2011). Similarly, supplementation of lycopene can significantly increase antioxidant capacity and decrease oxidative stress and the bone resorption marker N-telopeptide (NTx) in postmenopausal women (Mackinnon et al., 2011). In this study sixty postmenopausal women, 50-60 years old, were recruited. Participants either consumed regular tomato juice, lycopene-rich tomato juice, tomato Lyc-O-Mato lycopene capsules, or placebo capsules, twice daily for total lycopene intakes of 30, 70, 30, and 0 mg/day respectively for 4 months (Mackinnon et al., 2011). Serum collected and assayed for cross-linked aminoterminal N-telopeptide, carotenoid content, total antioxidant capacity (TAC), lipid, and protein oxidation. Remarkably, there were no toxicities were reported in 4 months of study (Mackinnon et al., 2011). There are several other natural extracts or herbal therapies, which have been successfully used against the bone loss. For example, use of Yin and Yang tonic formula in the treatment of osteopenia (Yang et al., 2011). This formulation was used in patients aged 55 to 75 with low bone mineral density. It was concluded that classic Yin and Yang tonic formula could increase the bone mass without any adverse effects (Yang et al., 2011). 6. Conclusions Compunds that provide effective prevention and therapy strategies with few side effects are highly desirable, in the patients suffering from bone loss. The traditional treatment of bone loss requires a life-long regimen of drugs, which can have a significant impact on patient's quality of life. Although there are numerous pharmacological treatments for bone loss, none seem to have a desirable level of efficacy without either high financial cost or side effects. Plant-derived products offer a promising alternative to traditional pharmacotherapy. Studies from our group and others from around the globe on natural agents have provided concrete evidence that natural agents have potential to either enhance the bone formation or prevent the bone loss. Several molecules derived from natural agents were found effective in either bone formation or prevention of bone loss such as resveratrol, curcumin, quercetin, withanolide, silibinin, wedelolactone, and silymarin. A number of natural agents are already in clinical trials and many more studies are underway. In addition, several medicinal herbs demonstrated therapeutic effects against osteoporosis in animal models. This is encouraging development for scientific community as well as for patients. Nonetheless many more agents require extensive investigation in various preclinical and clinical settings to prove their usefulness. One of the biggest challenges associated with natural agents are lack of studies on pharmacokinetics, formulation, and off target effects, in addition often time these agents fail in clinical trials. In addition to above challenges the American and International legal code, which prohibit the patenting of natural compounds, therefore, pharmaceutical industry has shown little motivation to pursue studies on natural agents. Perhaps, in years to come federal agencies will be more considerate about supporting such studies. Henceforth, scientist and medical researchers alike can begin to investigate natural products as the backbone for bone health. References Abdi et al., 2016 F. Abdi, Z. Alimoradi, P. Haqi, F. Mahdizad Effects of phytoestrogens on bone mineral density during the menopause transition: a systematic review of randomized, controlled trials Climacteric, 19 (6) (2016), pp. 535-545 CrossRefView Record in Scopus Adler, 2014 R.A. Adler Osteoporosis in men: a review Bone Res, 2 (2014), p. 14001 CrossRef Aggarwal, 2004 B.B. Aggarwal Nuclear factor-kappaB: the enemy within Cancer Cell, 6 (3) (2004), pp. 203-208 ArticleDownload PDFView Record in Scopus Aggarwal et al., 2006 Aggarwal B.B., S., S., Surh Y.J., 2006. The Molecular Targets and Therapeutic Uses of Curcumin in Health and Disease. Ahn et al., 2006 K.S. Ahn, G. Sethi, S. Shishodia, B. Sung, J.L. Arbiser, B.B. Aggarwal Honokiol potentiates apoptosis, suppresses osteoclastogenesis, and inhibits invasion through modulation of nuclear factor-kappaB activation pathway Mol. Cancer Res., 4 (9) (2006), pp. 621-633 CrossRefView Record in Scopus Ahn et al., 2008 K.S. Ahn, G. Sethi, M.M. Chaturvedi, B.B. Aggarwal Simvastatin, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, suppresses osteoclastogenesis induced by receptor activator of nuclear factor-kappaB ligand through modulation of NF-kappaB pathway Int. J. Cancer, 123 (8) (2008), pp. 1733-1740 CrossRef An et al., 2016 J. An, H. Yang, Q. Zhang, C. Liu, J. Zhao, L. Zhang, B. Chen Natural products for treatment of osteoporosis: The effects and mechanisms on promoting osteoblast-mediated bone formation Life Sci., 147 (2016), pp. 46-58 ArticleDownload PDFView Record in Scopus Ardawi et al., 2016 M.S. Ardawi, M.H. Badawoud, S.M. Hassan, A.A. Rouzi, J.M. Ardawi, N.M. AlNosani, M.H. Qari, S.A. Mousa Lycopene treatment against loss of bone mass, microarchitecture and strength in relation to regulatory mechanisms in a postmenopausal osteoporosis model Bone, 83 (2016), pp. 127-140 ArticleDownload PDFView Record in Scopus Armstrong et al., 2002 A.P. Armstrong, M.E. Tometsko, M. Glaccum, C.L. Sutherland, D. Cosman, W.C. Dougall A RANK/TRAF6-dependent signal transduction pathway is essential for osteoclast cytoskeletal organization and resorptive function J. Biol. Chem., 277 (46) (2002), pp. 44347-44356 CrossRefView Record in Scopus Atbinici et al., 2015 H. Atbinici, S. Sipahioglu, N. Aksoy, I. Baykara, U.E. Isikan Effects of salmon calcitonin treatment on serum and synovial fluid bone formation and resorption markers in osteoporosis patients Acta Orthop. Traumatol. Turc., 49 (2) (2015), pp. 160-165 View Record in Scopus Aubin et al., 2004 J. Aubin, A. Davy, P. Soriano In vivo convergence of BMP and MAPK signaling pathways: impact of differential Smad1 phosphorylation on development and homeostasis Genes Dev., 18 (12) (2004), pp. 1482-1494 CrossRefView Record in Scopus Balemans et al., 2007 W. Balemans, J.P. Devogelaer, E. Cleiren, E. Piters, E. Caussin, W. Van Hul Novel LRP5 missense mutation in a patient with a high bone mass phenotype results in decreased DKK1-mediated inhibition of Wnt signaling J. Bone Miner. Res., 22 (5) (2007), pp. 708-716 CrossRefView Record in Scopus Bandeira et al., 2016 L. Bandeira, E.M. Lewiecki, J.P. Bilezikian Pharmacodynamics and pharmacokinetics of oral salmon calcitonin in the treatment of osteoporosis Expert Opin. Drug Metab. Toxicol., 12 (6) (2016), pp. 681-689 CrossRefView Record in Scopus Bandyopadhyay et al., 2006 S. Bandyopadhyay, J.M. Lion, R. Mentaverri, D.A. Ricupero, S. Kamel, J.R. Romero, N. Chattopadhyay Attenuation of osteoclastogenesis and osteoclast function by apigenin Biochem. Pharmacol., 72 (2) (2006), pp. 184-197 ArticleDownload PDFView Record in Scopus Baron and Kneissel, 2013 R. Baron, M. Kneissel WNT signaling in bone homeostasis and disease: from human mutations to treatments Nat. Med., 19 (2) (2013), pp. 179-192 CrossRefView Record in Scopus Beekman et al., 2017 K.M. Beekman, A.G. Veldhuis-Vlug, M. den Heijer, M. Maas, A.M. Oleksik, M.W. Tanck, S.M. Ott, R.J. van 't Hof, P. Lips, P.H. Bisschop, N. Bravenboer The effect of raloxifene on bone marrow adipose tissue and bone turnover in postmenopausal women with osteoporosis Bone (2017), 10.1016/j.bone.2017.10.011 (In press) Belcaro et al., 2010 G. Belcaro, M.R. Cesarone, M. Dugall, L. Pellegrini, A. Ledda, M.G. Grossi, S. Togni, G. Appendino Efficacy and safety of Meriva(R), a curcumin-phosphatidylcholine complex, during extended administration in osteoarthritis patients Altern. Med. Rev., 15 (4) (2010), pp. 337-344 View Record in Scopus Bharti et al., 2004 A.C. Bharti, Y. Takada, B.B. Aggarwal Curcumin (diferuloylmethane) inhibits receptor activator of NF-kappa B ligand-induced NF-kappa B activation in osteoclast precursors and suppresses osteoclastogenesis J. Immunol., 172 (10) (2004), pp. 5940-5947 CrossRefView Record in Scopus Bian et al., 2012 Q. Bian, S.F. Liu, J.H. Huang, Z. Yang, D.Z. Tang, Q. Zhou, Y. Ning, Y.J. Zhao, S. Lu, Z.Y. Shen, Y.J. Wang Oleanolic acid exerts an osteoprotective effect in ovariectomy-induced osteoporotic rats and stimulates the osteoblastic differentiation of bone mesenchymal stem cells in vitro Menopause, 19 (2) (2012), pp. 225-233 CrossRefView Record in Scopus Binkley et al., 2014 N. Binkley, H. Bone, J.P. Gilligan, D.S. Krause Efficacy and safety of oral recombinant calcitonin tablets in postmenopausal women with low bone mass and increased fracture risk: a randomized, placebo-controlled trial Osteoporos. Int., 25 (11) (2014), pp. 2649-2656 CrossRefView Record in Scopus Boggon and Eck, 2004 T.J. Boggon, M.J. Eck Structure and regulation of Src family kinases Oncogene, 23 (48) (2004), pp. 7918-7927 CrossRefView Record in Scopus Boyce, 2013 B.F. Boyce Advances in the regulation of osteoclasts and osteoclast functions J. Dent. Res., 92 (10) (2013), pp. 860-867 CrossRefView Record in Scopus Boyce and Xing, 2007 B.F. Boyce, L. Xing Biology of RANK, RANKL, and osteoprotegerin Arthritis Res Ther, 9 (Suppl. 1) (2007), p. S1 CrossRefView Record in Scopus Boyce et al., 2015 B.F. Boyce, Y. Xiu, J. Li, L. Xing, Z. Yao NF-kappaB-Mediated Regulation of Osteoclastogenesis Endocrinol Metab (Seoul), 30 (1) (2015), pp. 35-44 CrossRefView Record in Scopus Boyle et al., 2003 W.J. Boyle, W.S. Simonet, D.L. Lacey Osteoclast differentiation and activation Nature, 423 (6937) (2003), pp. 337-342 CrossRefView Record in Scopus Broege et al., 2013 A. Broege, L. Pham, E.D. Jensen, A. Emery, T.H. Huang, M. Stemig, H. Beppu, A. Petryk, M. O'Connor, K. Mansky, R. Gopalakrishnan Bone morphogenetic proteins signal via SMAD and mitogen-activated protein (MAP) kinase pathways at distinct times during osteoclastogenesis J. Biol. Chem., 288 (52) (2013), pp. 37230-37240 CrossRefView Record in Scopus Burgers and Williams, 2013 T.A. Burgers, B.O. Williams Regulation of Wnt/beta-catenin signaling within and from osteocytes Bone, 54 (2) (2013), pp. 244-249 ArticleDownload PDFView Record in Scopus Cai and Liu, 2016 H. Cai, A. Liu Spop promotes skeletal development and homeostasis by positively regulating Ihh signaling Proc. Natl. Acad. Sci. U. S. A., 113 (51) (2016), pp. 14751-14756 CrossRefView Record in Scopus Canalis, 2018 E. Canalis MANAGEMENT OF ENDOCRINE DISEASE: Novel Anabolic Treatments for Osteoporosis Eur. J. Endocrinol., 178 (2) (2018), pp. R33-R44 CrossRefView Record in Scopus Cappellen et al., 2002 D. Cappellen, N.H. Luong-Nguyen, S. Bongiovanni, O. Grenet, C. Wanke, M. Susa Transcriptional program of mouse osteoclast differentiation governed by the macrophage colony-stimulating factor and the ligand for the receptor activator of NFkappa B J. Biol. Chem., 277 (24) (2002), pp. 21971-21982 CrossRefView Record in Scopus Casado-Diaz et al., 2016 A. Casado-Diaz, J. Anter, G. Dorado, J.M. Quesada-Gomez Effects of quercetin, a natural phenolic compound, in the differentiation of human mesenchymal stem cells (MSC) into adipocytes and osteoblasts J. Nutr. Biochem., 32 (2016), pp. 151-162 ArticleDownload PDFView Record in Scopus Chambers, 2000 T.J. Chambers Regulation of the differentiation and function of osteoclasts J. Pathol., 192 (1) (2000), pp. 4-13 CrossRefView Record in Scopus Chandran and Goel, 2012 B. Chandran, A. Goel A randomized, pilot study to assess the efficacy and safety of curcumin in patients with active rheumatoid arthritis Phytother. Res., 26 (11) (2012), pp. 1719-1725 CrossRefView Record in Scopus Chen et al., 2010 Y.C. Chen, D.M. Sosnoski, A.M. Mastro Breast cancer metastasis to the bone: mechanisms of bone loss Breast Cancer Res., 12 (6) (2010), p. 215 View Record in Scopus Chen et al., 2012 G. Chen, C. Deng, Y.P. Li TGF-beta and BMP signaling in osteoblast differentiation and bone formation Int. J. Biol. Sci., 8 (2) (2012), pp. 272-288 CrossRefView Record in Scopus Chen et al., 2016 Z. Chen, J. Xue, T. Shen, S. Mu, Q. Fu Curcumin alleviates glucocorticoid-induced osteoporosis through the regulation of the Wnt signaling pathway Int. J. Mol. Med., 37 (2) (2016), pp. 329-338 CrossRefView Record in Scopus Chen et al., 2017 X. Chen, S. Ren, G. Zhu, Z. Wang, X. Wen Emodin suppresses cadmium-induced osteoporosis by inhibiting osteoclast formation Environ. Toxicol. Pharmacol., 54 (2017), pp. 162-168 ArticleDownload PDFView Record in Scopus Cheung et al., 2006 W.M. Cheung, L.Y. Jin, D.K. Smith, P.T. Cheung, E.Y. Kwan, L. Low, A.W. Kung A family with osteoporosis pseudoglioma syndrome due to compound heterozygosity of two novel mutations in the LRP5 gene Bone, 39 (3) (2006), pp. 470-476 ArticleDownload PDFView Record in Scopus Chin, 2016 K.Y. Chin The spice for joint inflammation: anti-inflammatory role of curcumin in treating osteoarthritis Drug Des Devel Ther, 10 (2016), pp. 3029-3042 CrossRefView Record in Scopus Choi, 2011 E.M. Choi Honokiol isolated from Magnolia officinalis stimulates osteoblast function and inhibits the release of bone-resorbing mediators Int. Immunopharmacol., 11 (10) (2011), pp. 1541-1545 ArticleDownload PDFView Record in Scopus Choi et al., 2012 S.W. Choi, Y.J. Son, J.M. Yun, S.H. Kim Fisetin Inhibits Osteoclast Differentiation via Downregulation of p38 and c-Fos-NFATc1 Signaling Pathways Evid. Based Complement. Alternat. Med., 2012 (2012), p. 810563 View Record in Scopus Chung et al., 2001 U.I. Chung, E. Schipani, A.P. McMahon, H.M. Kronenberg Indian hedgehog couples chondrogenesis to osteogenesis in endochondral bone development J. Clin. Invest., 107 (3) (2001), pp. 295-304 CrossRefView Record in Scopus Chung et al., 2017 H.J. Chung, W.K. Kim, J. Oh, M.R. Kim, J.S. Shin, J. Lee, I.H. Ha, S.K. Lee Anti-Osteoporotic Activity of Harpagoside by Upregulation of the BMP2 and Wnt Signaling Pathways in Osteoblasts and Suppression of Differentiation in Osteoclasts J. Nat. Prod., 80 (2) (2017), pp. 434-442 CrossRefView Record in Scopus Clementini et al., 2014 M. Clementini, P.H. Rossetti, D. Penarrocha, C. Micarelli, W.C. Bonachela, L. Canullo Systemic risk factors for peri-implant bone loss: a systematic review and meta-analysis Int. J. Oral Maxillofac. Surg., 43 (3) (2014), pp. 323-334 ArticleDownload PDFView Record in Scopus Cotter and Cashman, 2003 A. Cotter, K.D. Cashman Genistein appears to prevent early postmenopausal bone loss as effectively as hormone replacement therapy Nutr. Rev., 61 (10) (2003), pp. 346-351 CrossRefView Record in Scopus Crasto et al., 2013 G.J. Crasto, N. Kartner, Y. Yao, K. Li, L. Bullock, A. Datti, M.F. Manolson Luteolin inhibition of V-ATPase a3-d2 interaction decreases osteoclast resorptive activity J. Cell. Biochem., 114 (4) (2013), pp. 929-941 CrossRefView Record in Scopus Cummings et al., 2018 S.R. Cummings, S. Ferrari, R. Eastell, N. Gilchrist, J.E. Beck Jensen, M. McClung, C. Roux, O. Torring, I. Valter, A.T. Wang, J.P. Brown Vertebral Fractures Following Discontinuation of Denosumab: a Post-hoc Analysis of the Randomized Placebo-controlled FREEDOM Trial and its Extension J. Bone Miner. Res., 33 (2) (2018), pp. 190-198 View Record in Scopus Dai et al., 2013 J. Dai, Y. Li, H. Zhou, J. Chen, M. Chen, Z. Xiao Genistein promotion of osteogenic differentiation through BMP2/SMAD5/RUNX2 signaling Int. J. Biol. Sci., 9 (10) (2013), pp. 1089-1098 CrossRefView Record in Scopus Daily et al., 2016 J.W. Daily, M. Yang, S. Park Efficacy of Turmeric Extracts and Curcumin for Alleviating the Symptoms of Joint Arthritis: A Systematic Review and Meta-Analysis of Randomized Clinical Trials J. Med. Food, 19 (8) (2016), pp. 717-729 CrossRefView Record in Scopus Darnay et al., 1998 B.G. Darnay, V. Haridas, J. Ni, P.A. Moore, B.B. Aggarwal Characterization of the intracellular domain of receptor activator of NF-kappaB (RANK). Interaction with tumor necrosis factor receptor-associated factors and activation of NF-kappab and c-Jun N-terminal kinase J. Biol. Chem., 273 (32) (1998), pp. 20551-20555 CrossRefView Record in Scopus Das and Crockett, 2013 S. Das, J.C. Crockett Osteoporosis - a current view of pharmacological prevention and treatment Drug Des Devel Ther, 7 (2013), pp. 435-448 View Record in Scopus Dathe et al., 2009 K. Dathe, K.W. Kjaer, A. Brehm, P. Meinecke, P. Nurnberg, J.C. Neto, D. Brunoni, N. Tommerup, C.E. Ott, E. Klopocki, P. Seemann, S. Mundlos Duplications involving a conserved regulatory element downstream of BMP2 are associated with brachydactyly type A2 Am. J. Hum. Genet., 84 (4) (2009), pp. 483-492 ArticleDownload PDFView Record in Scopus Day et al., 2005 T.F. Day, X. Guo, L. Garrett-Beal, Y. Yang Wnt/beta-catenin signaling in mesenchymal progenitors controls osteoblast and chondrocyte differentiation during vertebrate skeletogenesis Dev. Cell, 8 (5) (2005), pp. 739-750 ArticleDownload PDFView Record in Scopus Deepak et al., 2015a V. Deepak, A. Kasonga, M.C. Kruger, M. Coetzee Inhibitory effects of eugenol on RANKL-induced osteoclast formation via attenuation of NF-kappaB and MAPK pathways Connect. Tissue Res., 56 (3) (2015), pp. 195-203 CrossRefView Record in Scopus Deepak et al., 2015b V. Deepak, M.C. Kruger, A. Joubert, M. Coetzee Piperine alleviates osteoclast formation through the p38/c-Fos/NFATc1 signaling axis Biofactors, 41 (6) (2015), pp. 403-413 CrossRefView Record in Scopus Dempster et al., 2018 D.W. Dempster, H. Zhou, R.R. Recker, J.P. Brown, C.P. Recknor, E.M. Lewiecki, P.D. Miller, S.D. Rao, D.L. Kendler, R. Lindsay, J.H. Krege, J. Alam, K.A. Taylor, T.E. Melby, V.A. Ruff Remodeling- and Modeling-Based Bone Formation with Teriparatide versus Denosumab: A Longitudinal Analysis from Baseline to 3 Months in the AVA Study J. Bone Miner. Res., 33 (2) (2018), pp. 298-306 View Record in Scopus Deng et al., 2014 L. Deng, Y. Ding, Y. Peng, Y. Wu, J. Fan, W. Li, R. Yang, M. Yang, Q. Fu gamma-Tocotrienol protects against ovariectomy-induced bone loss via mevalonate pathway as HMG-CoA reductase inhibitor Bone, 67 (2014), pp. 200-207 ArticleDownload PDFView Record in Scopus Derakhshanian et al., 2013 H. Derakhshanian, M. Djalali, A. Djazayery, K. Nourijelyani, S. Ghadbeigi, H. Pishva, A. Saedisomeolia, A. Bahremand, A.R. Dehpour Quercetin prevents experimental glucocorticoid-induced osteoporosis: a comparative study with alendronate Can. J. Physiol. Pharmacol., 91 (5) (2013), pp. 380-385 CrossRefView Record in Scopus Derynck and Zhang, 2003 R. Derynck, Y.E. Zhang Smad-dependent and Smad-independent pathways in TGF-beta family signalling Nature, 425 (6958) (2003), pp. 577-584 CrossRefView Record in Scopus Destaing et al., 2008 O. Destaing, A. Sanjay, C. Itzstein, W.C. Horne, D. Toomre, P. De Camilli, R. Baron The tyrosine kinase activity of c-Src regulates actin dynamics and organization of podosomes in osteoclasts Mol. Biol. Cell, 19 (1) (2008), pp. 394-404 CrossRefView Record in Scopus Dong et al., 2010 L. Dong, S. Xia, F. Gao, D. Zhang, J. Chen, J. Zhang 3,3'-Diindolylmethane attenuates experimental arthritis and osteoclastogenesis Biochem. Pharmacol., 79 (5) (2010), pp. 715-721 ArticleDownload PDFView Record in Scopus Dosier et al., 2012 C.R. Dosier, C.P. Erdman, J.H. Park, Z. Schwartz, B.D. Boyan, R.E. Guldberg Resveratrol effect on osteogenic differentiation of rat and human adipose derived stem cells in a 3-D culture environment J. Mech. Behav. Biomed. Mater., 11 (2012), pp. 112-122 ArticleDownload PDFView Record in Scopus Dougall et al., 1999 W.C. Dougall, M. Glaccum, K. Charrier, K. Rohrbach, K. Brasel, T. De Smedt, E. Daro, J. Smith, M.E. Tometsko, C.R. Maliszewski, A. Armstrong, V. Shen, S. Bain, D. Cosman, D. Anderson, P.J. Morrissey, J.J. Peschon, J. Schuh RANK is essential for osteoclast and lymph node development Genes Dev., 13 (18) (1999), pp. 2412-2424 CrossRefView Record in Scopus Duan et al., 2014 W. Duan, Q. Wang, F. Li, C. Xiang, L. Zhou, J. Xu, H. Feng, X. Wei Anti-catabolic effect of caffeic acid phenethyl ester, an active component of honeybee propolis on bone loss in ovariectomized mice: a micro-computed tomography study and histological analysis Chin. Med. J., 127 (22) (2014), pp. 3932-3936 View Record in Scopus Edwards and Mundy, 2008 C.M. Edwards, G.R. Mundy Eph receptors and ephrin signaling pathways: a role in bone homeostasis Int. J. Med. Sci., 5 (5) (2008), pp. 263-272 CrossRefView Record in Scopus Fan et al., 2015 J.Z. Fan, X. Yang, Z.G. Bi The effects of 6-gingerol on proliferation, differentiation, and maturation of osteoblast-like MG-63 cells Braz. J. Med. Biol. Res., 48 (7) (2015), pp. 637-643 CrossRefView Record in Scopus Feng and Teitelbaum, 2013 X. Feng, S.L. Teitelbaum Osteoclasts: New Insights Bone Res, 1 (1) (2013), pp. 11-26 CrossRef Fernandez-Garcia et al., 2008 D. Fernandez-Garcia, M. Munoz-Torres, P. Mezquita-Raya, M. de la Higuera, G. Alonso, R. Reyes-Garcia, A.S. Ochoa, M.E. Ruiz-Requena, J.D. Luna, F. Escobar-Jimenez Effects of raloxifene therapy on circulating osteoprotegerin and RANK ligand levels in post-menopausal osteoporosis J. Endocrinol. Investig., 31 (5) (2008), pp. 416-421 CrossRefView Record in Scopus Franceschi et al., 2003 R.T. Franceschi, G. Xiao, D. Jiang, R. Gopalakrishnan, S. Yang, E. Reith Multiple signaling pathways converge on the Cbfa1/Runx2 transcription factor to regulate osteoblast differentiation Connect. Tissue Res., 44 (Suppl. 1) (2003), pp. 109-116 CrossRefView Record in Scopus Franzoso et al., 1997 G. Franzoso, L. Carlson, L. Xing, L. Poljak, E.W. Shores, K.D. Brown, A. Leonardi, T. Tran, B.F. Boyce, U. Siebenlist Requirement for NF-kappaB in osteoclast and B-cell development Genes Dev., 11 (24) (1997), pp. 3482-3496 CrossRefView Record in Scopus Gao et al., 2017 J. Gao, C. Gao, H. Li, G.S. Wang, C. Xu, J. Ran Effect of zoledronic acid on reducing femoral bone mineral density loss following total hip arthroplasty: A meta-analysis from randomized controlled trails Int. J. Surg., 47 (2017), pp. 116-126 ArticleDownload PDFView Record in Scopus Glass II et al., 2005 D.A. Glass II, P. Bialek, J.D. Ahn, M. Starbuck, M.S. Patel, H. Clevers, M.M. Taketo, F. Long, A.P. McMahon, R.A. Lang, G. Karsenty Canonical Wnt signaling in differentiated osteoblasts controls osteoclast differentiation Dev. Cell, 8 (5) (2005), pp. 751-764 ArticleDownload PDFView Record in Scopus Goetz et al., 2017 L.G. Goetz, R. Mamillapalli, M.J. Devlin, A.E. Robbins, M. Majidi-Zolbin, H.S. Taylor Cross-sex testosterone therapy in ovariectomized mice: addition of low-dose estrogen preserves bone architecture Am. J. Physiol. Endocrinol. Metab., 313 (5) (2017), pp. E540-E551 CrossRefView Record in Scopus Gomes-Filho et al., 2015 J.E. Gomes-Filho, M.T. Wayama, R.C. Dornelles, E. Ervolino, G.H. Yamanari, C.S. Lodi, G. Sivieri-Araujo, E. Dezan-Junior, L.T. Cintra Raloxifene modulates regulators of osteoclastogenesis and angiogenesis in an oestrogen deficiency periapical lesion model Int. Endod. J., 48 (11) (2015), pp. 1059-1068 CrossRefView Record in Scopus Gomez-Florit et al., 2015 M. Gomez-Florit, M. Monjo, J.M. Ramis Quercitrin for periodontal regeneration: effects on human gingival fibroblasts and mesenchymal stem cells Sci. Rep., 5 (2015), p. 16593 View Record in Scopus Goto et al., 2015 T. Goto, K. Hagiwara, N. Shirai, K. Yoshida, H. Hagiwara Apigenin inhibits osteoblastogenesis and osteoclastogenesis and prevents bone loss in ovariectomized mice Cytotechnology, 67 (2) (2015), pp. 357-365 CrossRefView Record in Scopus Greenspan et al., 2018 S.L. Greenspan, K. Vujevich, C. Britton, A. Herradura, G. Gruen, I. Tarkin, P. Siska, B. Hamlin, S. Perera Teriparatide for treatment of patients with bisphosphonate-associated atypical fracture of the femur Osteoporos. Int., 29 (2) (2018), pp. 501-506 View Record in Scopus Grigg et al., 2017 A. Grigg, B. Butcher, B. Khodr, A. Bajel, M. Hertzberg, S. Patil, A.B. D'Souza, P. Ganly, P. Ebeling, E. Wong An individualised risk-adapted protocol of pre- and post transplant zoledronic acid reduces bone loss after allogeneic stem cell transplantation: results of a phase II prospective trial Bone Marrow Transplant., 52 (9) (2017), pp. 1288-1293 CrossRefView Record in Scopus Gu et al., 2012 Q. Gu, Y. Cai, C. Huang, Q. Shi, H. Yang Curcumin increases rat mesenchymal stem cell osteoblast differentiation but inhibits adipocyte differentiation Pharmacogn. Mag., 8 (31) (2012), pp. 202-208 View Record in Scopus Guo et al., 2012 C. Guo, G.Q. Hou, X.D. Li, X. Xia, D.X. Liu, D.Y. Huang, S.X. Du Quercetin triggers apoptosis of lipopolysaccharide (LPS)-induced osteoclasts and inhibits bone resorption in RAW264.7 cells Cell. Physiol. Biochem., 30 (1) (2012), pp. 123-136 CrossRefView Record in Scopus Hasegawa et al., 2010 S. Hasegawa, T. Yonezawa, J.Y. Ahn, B.Y. Cha, T. Teruya, M. Takami, K. Yagasaki, K. Nagai, J.T. Woo Honokiol inhibits osteoclast differentiation and function in vitro Biol. Pharm. Bull., 33 (3) (2010), pp. 487-492 CrossRefView Record in Scopus Hayden and Ghosh, 2008 M.S. Hayden, S. Ghosh Shared principles in NF-kappaB signaling Cell, 132 (3) (2008), pp. 344-362 ArticleDownload PDFView Record in Scopus Heim et al., 2004 M. Heim, O. Frank, G. Kampmann, N. Sochocky, T. Pennimpede, P. Fuchs, W. Hunziker, P. Weber, I. Martin, I. Bendik The phytoestrogen genistein enhances osteogenesis and represses adipogenic differentiation of human primary bone marrow stromal cells Endocrinology, 145 (2) (2004), pp. 848-859 CrossRefView Record in Scopus Henrotin et al., 2014 Y. Henrotin, M. Gharbi, Y. Dierckxsens, F. Priem, M. Marty, L. Seidel, A. Albert, E. Heuse, V. Bonnet, C. Castermans Decrease of a specific biomarker of collagen degradation in osteoarthritis, Coll2-1, by treatment with highly bioavailable curcumin during an exploratory clinical trial BMC Complement. Altern. Med., 14 (2014), p. 159 Hill et al., 2005 T.P. Hill, D. Spater, M.M. Taketo, W. Birchmeier, C. Hartmann Canonical Wnt/beta-catenin signaling prevents osteoblasts from differentiating into chondrocytes Dev. Cell, 8 (5) (2005), pp. 727-738 ArticleDownload PDFView Record in Scopus Hou et al., 2016 M. Hou, Y. Song, Z. Li, C. Luo, J.S. Ou, H. Yu, J. Yan, L. Lu Curcumin attenuates osteogenic differentiation and calcification of rat vascular smooth muscle cells Mol. Cell. Biochem., 420 (1-2) (2016), pp. 151-160 CrossRefView Record in Scopus Hsu et al., 2011 Y.C. Hsu, C.P. Cheng, D.M. Chang Plectranthus amboinicus attenuates inflammatory bone erosion in mice with collagen-induced arthritis by downregulation of RANKL-induced NFATc1 expression J. Rheumatol., 38 (9) (2011), pp. 1844-1857 CrossRefView Record in Scopus Hu et al., 2008 J.P. Hu, K. Nishishita, E. Sakai, H. Yoshida, Y. Kato, T. Tsukuba, K. Okamoto Berberine inhibits RANKL-induced osteoclast formation and survival through suppressing the NF-kappaB and Akt pathways Eur. J. Pharmacol., 580 (1-2) (2008), pp. 70-79 ArticleDownload PDFView Record in Scopus Hu et al., 2017 X. Hu, Z. Ping, M. Gan, Y. Tao, L. Wang, J. Shi, X. Wu, W. Zhang, H. Yang, Y. Xu, Z. Wang, D. Geng Theaflavin-3,3'-digallate represses osteoclastogenesis and prevents wear debris-induced osteolysis via suppression of ERK pathway Acta Biomater., 48 (2017), pp. 479-488 ArticleDownload PDFView Record in Scopus Ichikawa and Aggarwal, 2006 H. Ichikawa, B.B. Aggarwal Guggulsterone inhibits osteoclastogenesis induced by receptor activator of nuclear factor-kappaB ligand and by tumor cells by suppressing nuclear factor-kappaB activation Clin. Cancer Res., 12 (2) (2006), pp. 662-668 CrossRefView Record in Scopus Ichikawa et al., 2006a H. Ichikawa, A. Murakami, B.B. Aggarwal 1'-Acetoxychavicol acetate inhibits RANKL-induced osteoclastic differentiation of RAW 264.7 monocytic cells by suppressing nuclear factor-kappaB activation Mol. Cancer Res., 4 (4) (2006), pp. 275-281 CrossRefView Record in Scopus Ichikawa et al., 2006b H. Ichikawa, M.S. Nair, Y. Takada, D.B. Sheeja, M.A. Kumar, O.V. Oommen, B.B. Aggarwal Isodeoxyelephantopin, a novel sesquiterpene lactone, potentiates apoptosis, inhibits invasion, and abolishes osteoclastogenesis through suppression of nuclear factor-kappaB (nf-kappaB) activation and nf-kappaB-regulated gene expression Clin. Cancer Res., 12 (19) (2006), pp. 5910-5918 CrossRefView Record in Scopus Ichikawa et al., 2006c H. Ichikawa, Y. Takada, S. Shishodia, B. Jayaprakasam, M.G. Nair, B.B. Aggarwal Withanolides potentiate apoptosis, inhibit invasion, and abolish osteoclastogenesis through suppression of nuclear factor-kappaB (NF-kappaB) activation and NF-kappaB-regulated gene expression Mol. Cancer Ther., 5 (6) (2006), pp. 1434-1445 CrossRefView Record in Scopus Ichikawa et al., 2007 H. Ichikawa, Y. Nakamura, Y. Kashiwada, B.B. Aggarwal Anticancer drugs designed by mother nature: ancient drugs but modern targets Curr. Pharm. Des., 13 (33) (2007), pp. 3400-3416 CrossRefView Record in Scopus Iimura et al., 2014 Y. Iimura, U. Agata, S. Takeda, Y. Kobayashi, S. Yoshida, I. Ezawa, N. Omi Lycopene intake facilitates the increase of bone mineral density in growing female rats J. Nutr. Sci. Vitaminol. (Tokyo), 60 (2) (2014), pp. 101-107 CrossRefView Record in Scopus Iimura et al., 2015 Y. Iimura, U. Agata, S. Takeda, Y. Kobayashi, S. Yoshida, I. Ezawa, N. Omi The protective effect of lycopene intake on bone loss in ovariectomized rats J. Bone Miner. Metab., 33 (3) (2015), pp. 270-278 CrossRefView Record in Scopus Im et al., 2016 N.K. Im, D.S. Lee, S.R. Lee, G.S. Jeong Lupeol Isolated from Sorbus commixta Suppresses 1alpha,25-(OH)2D3-Mediated Osteoclast Differentiation and Bone Loss in Vitro and in Vivo J. Nat. Prod., 79 (2) (2016), pp. 412-420 CrossRefView Record in Scopus Iniguez-Ariza and Clarke, 2015 N.M. Iniguez-Ariza, B.L. Clarke Bone biology, signaling pathways, and therapeutic targets for osteoporosis Maturitas, 82 (2) (2015), pp. 245-255 ArticleDownload PDFView Record in Scopus Iotsova et al., 1997 V. Iotsova, J. Caamano, J. Loy, Y. Yang, A. Lewin, R. Bravo Osteopetrosis in mice lacking NF-kappaB1 and NF-kappaB2 Nat. Med., 3 (11) (1997), pp. 1285-1289 CrossRefView Record in Scopus Jacob et al., 2006 A.L. Jacob, C. Smith, J. Partanen, D.M. Ornitz Fibroblast growth factor receptor 1 signaling in the osteo-chondrogenic cell lineage regulates sequential steps of osteoblast maturation Dev. Biol., 296 (2) (2006), pp. 315-328 ArticleDownload PDFView Record in Scopus Javed et al., 2008 A. Javed, J.S. Bae, F. Afzal, S. Gutierrez, J. Pratap, S.K. Zaidi, Y. Lou, A.J. van Wijnen, J.L. Stein, G.S. Stein, J.B. Lian Structural coupling of Smad and Runx2 for execution of the BMP2 osteogenic signal J. Biol. Chem., 283 (13) (2008), pp. 8412-8422 CrossRefView Record in Scopus Jiang et al., 2015a C. Jiang, F. Xiao, X. Gu, Z. Zhai, X. Liu, W. Wang, T. Tang, Y. Wang, Z. Zhu, K. Dai, A. Qin, J. Wang Inhibitory effects of ursolic acid on osteoclastogenesis and titanium particle-induced osteolysis are mediated primarily via suppression of NF-kappaB signaling Biochimie, 111 (2015), pp. 107-118 ArticleDownload PDFView Record in Scopus Jiang et al., 2015b T. Jiang, B. Zhou, L. Huang, H. Wu, J. Huang, T. Liang, H. Liu, L. Zheng, J. Zhao Andrographolide Exerts Pro-Osteogenic Effect by Activation of Wnt/beta-Catenin Signaling Pathway in Vitro Cell. Physiol. Biochem., 36 (6) (2015), pp. 2327-2339 CrossRefView Record in Scopus Johnson and Wilkie, 2011 D. Johnson, A.O. Wilkie Craniosynostosis Eur. J. Hum. Genet., 19 (4) (2011), pp. 369-376 CrossRefView Record in Scopus Joo et al., 2004 S.S. Joo, T.J. Won, H.C. Kang, D.I. Lee Isoflavones extracted from Sophorae fructus upregulate IGF-I and TGF-beta and inhibit osteoclastogenesis in rat bone marrow cells Arch. Pharm. Res., 27 (1) (2004), pp. 99-105 CrossRefView Record in Scopus Kaneko et al., 2017 T. Kaneko, K. Okamura, Y. Yonemoto, C. Okura, T. Suto, M. Tachibana, Y. Tamura, M. Inoue, H. Chikuda Short-term daily teriparatide in patients with rheumatoid arthritis Mod. Rheumatol. (2017), pp. 1-6 CrossRef Kang et al., 2007 S. Kang, C.N. Bennett, I. Gerin, L.A. Rapp, K.D. Hankenson, O.A. Macdougald Wnt signaling stimulates osteoblastogenesis of mesenchymal precursors by suppressing CCAAT/enhancer-binding protein alpha and peroxisome proliferator-activated receptor gamma J. Biol. Chem., 282 (19) (2007), pp. 14515-14524 CrossRefView Record in Scopus Kang et al., 2014 D.M. Kang, K.H. Yoon, J.Y. Kim, J.M. Oh, M. Lee, S.T. Jung, S.K. Juhng, Y.H. Lee CT imaging biomarker for evaluation of emodin as a potential drug on LPS-mediated osteoporosis mice Acad. Radiol., 21 (4) (2014), pp. 457-462 ArticleDownload PDFView Record in Scopus Karin and Lin, 2002 M. Karin, A. Lin NF-kappaB at the crossroads of life and death Nat. Immunol., 3 (3) (2002), pp. 221-227 CrossRefView Record in Scopus Katz et al., 2013 L.H. Katz, Y. Li, J.S. Chen, N.M. Munoz, A. Majumdar, J. Chen, L. Mishra Targeting TGF-beta signaling in cancer Expert Opin. Ther. Targets, 17 (7) (2013), pp. 743-760 CrossRefView Record in Scopus Kavitha et al., 2014 C.V. Kavitha, G. Deep, S.C. Gangar, A.K. Jain, C. Agarwal, R. Agarwal Silibinin inhibits prostate cancer cells- and RANKL-induced osteoclastogenesis by targeting NFATc1, NF-kappaB, and AP-1 activation in RAW264.7 cells Mol. Carcinog., 53 (3) (2014), pp. 169-180 CrossRefView Record in Scopus Ke et al., 2015 K. Ke, O.J. Sul, M. Rajasekaran, H.S. Choi MicroRNA-183 increases osteoclastogenesis by repressing heme oxygenase-1 Bone, 81 (2015), pp. 237-246 ArticleDownload PDFView Record in Scopus Khalid and Krum, 2016 A.B. Khalid, S.A. Krum Estrogen receptors alpha and beta in bone Bone, 87 (2016), pp. 130-135 ArticleDownload PDFView Record in Scopus Khanna et al., 2007 D. Khanna, G. Sethi, K.S. Ahn, M.K. Pandey, A.B. Kunnumakkara, B. Sung, A. Aggarwal, B.B. Aggarwal Natural products as a gold mine for arthritis treatment Curr. Opin. Pharmacol., 7 (3) (2007), pp. 344-351 ArticleDownload PDFView Record in Scopus Khedgikar et al., 2013 V. Khedgikar, P. Kushwaha, J. Gautam, A. Verma, B. Changkija, A. Kumar, S. Sharma, G.K. Nagar, D. Singh, P.K. Trivedi, N.S. Sangwan, P.R. Mishra, R. Trivedi Withaferin A: a proteasomal inhibitor promotes healing after injury and exerts anabolic effect on osteoporotic bone Cell Death Dis., 4 (2013), Article e778 CrossRef Kim and Kim, 2016 J.H. Kim, N. Kim Signaling Pathways in Osteoclast Differentiation Chonnam Med J, 52 (1) (2016), pp. 12-17 ArticleDownload PDFCrossRefView Record in Scopus Kim et al., 2005a N. Kim, Y. Kadono, M. Takami, J. Lee, S.H. Lee, F. Okada, J.H. Kim, T. Kobayashi, P.R. Odgren, H. Nakano, W.C. Yeh, S.K. Lee, J.A. Lorenzo, Y. Choi Osteoclast differentiation independent of the TRANCE-RANK-TRAF6 axis J. Exp. Med., 202 (5) (2005), pp. 589-595 CrossRefView Record in Scopus Kim et al., 2005b S.J. Kim, S.Y. Kang, H.H. Shin, H.S. Choi Sulforaphane inhibits osteoclastogenesis by inhibiting nuclear factor-kappaB Mol. Cell, 20 (3) (2005), pp. 364-370 View Record in Scopus Kim et al., 2006 Y.J. Kim, Y.C. Bae, K.T. Suh, J.S. Jung Quercetin, a flavonoid, inhibits proliferation and increases osteogenic differentiation in human adipose stromal cells Biochem. Pharmacol., 72 (10) (2006), pp. 1268-1278 ArticleDownload PDFView Record in Scopus Kim et al., 2009 J.H. Kim, K. Kim, H.M. Jin, I. Song, B.U. Youn, J. Lee, N. Kim Silibinin inhibits osteoclast differentiation mediated by TNF family members Mol. Cell, 28 (3) (2009), pp. 201-207 CrossRefView Record in Scopus Kim et al., 2011a T.H. Kim, J.W. Jung, B.G. Ha, J.M. Hong, E.K. Park, H.J. Kim, S.Y. Kim The effects of luteolin on osteoclast differentiation, function in vitro and ovariectomy-induced bone loss J. Nutr. Biochem., 22 (1) (2011), pp. 8-15 ArticleDownload PDFView Record in Scopus Kim et al., 2011b W.K. Kim, K. Ke, O.J. Sul, H.J. Kim, S.H. Kim, M.H. Lee, H.J. Kim, S.Y. Kim, H.T. Chung, H.S. Choi Curcumin protects against ovariectomy-induced bone loss and decreases osteoclastogenesis J. Cell. Biochem., 112 (11) (2011), pp. 3159-3166 CrossRefView Record in Scopus Kim et al., 2012 J.H. Kim, S.C. Gupta, B. Park, V.R. Yadav, B.B. Aggarwal Turmeric (Curcuma longa) inhibits inflammatory nuclear factor (NF)-kappaB and NF-kappaB-regulated gene products and induces death receptors leading to suppressed proliferation, induced chemosensitization, and suppressed osteoclastogenesis Mol. Nutr. Food Res., 56 (3) (2012), pp. 454-465 CrossRefView Record in Scopus Kim et al., 2012a J.L. Kim, S.W. Kang, M.K. Kang, J.H. Gong, E.S. Lee, S.J. Han, Y.H. Kang Osteoblastogenesis and osteoprotection enhanced by flavonolignan silibinin in osteoblasts and osteoclasts J. Cell. Biochem., 113 (1) (2012), pp. 247-259 CrossRefView Record in Scopus Kim et al., 2012b J.L. Kim, S.H. Park, D. Jeong, J.S. Nam, Y.H. Kang Osteogenic activity of silymarin through enhancement of alkaline phosphatase and osteocalcin in osteoblasts and tibia-fractured mice Exp Biol Med (Maywood), 237 (4) (2012), pp. 417-428 CrossRefView Record in Scopus Kim et al., 2014a H.J. Kim, J.M. Hong, H.J. Yoon, B.M. Kwon, J.Y. Choi, I.K. Lee, S.Y. Kim Inhibitory effects of obovatol on osteoclast differentiation and bone resorption Eur. J. Pharmacol., 723 (2014), pp. 473-480 ArticleDownload PDFView Record in Scopus Kim et al., 2014b Y.H. Kim, J.L. Kim, E.J. Lee, S.H. Park, S.Y. Han, S.A. Kang, Y.H. Kang Fisetin antagonizes cell fusion, cytoskeletal organization and bone resorption in RANKL-differentiated murine macrophages J. Nutr. Biochem., 25 (3) (2014), pp. 295-303 ArticleDownload PDFView Record in Scopus Kim et al., 2015a H.N. Kim, L. Han, S. Iyer, R. de Cabo, H. Zhao, C.A. O'Brien, S.C. Manolagas, M. Almeida Sirtuin1 Suppresses Osteoclastogenesis by Deacetylating FoxOs Mol. Endocrinol., 29 (10) (2015), pp. 1498-1509 CrossRefView Record in Scopus Kim et al., 2015b J.Y. Kim, S.H. Park, J.M. Baek, M. Erkhembaatar, M.S. Kim, K.H. Yoon, J. Oh, M.S. Lee Harpagoside Inhibits RANKL-Induced Osteoclastogenesis via Syk-Btk-PLCgamma2-Ca(2+) Signaling Pathway and Prevents Inflammation-Mediated Bone Loss J. Nat. Prod., 78 (9) (2015), pp. 2167-2174 CrossRefView Record in Scopus King et al., 2015 T.J. King, T. Shandala, A.M. Lee, B.K. Foster, K.M. Chen, P.R. Howe, C.J. Xian Potential Effects of Phytoestrogen Genistein in Modulating Acute Methotrexate Chemotherapy-Induced Osteoclastogenesis and Bone Damage in Rats Int. J. Mol. Sci., 16 (8) (2015), pp. 18293-18311 CrossRefView Record in Scopus Kling et al., 2014 J.M. Kling, B.L. Clarke, N.P. Sandhu Osteoporosis prevention, screening, and treatment: a review J. Women's Health (Larchmt), 23 (7) (2014), pp. 563-572 CrossRefView Record in Scopus Ko, 2016 J.M. Ko Genetic Syndromes Associated with Craniosynostosis J Korean Neurosurg Soc, 59 (3) (2016), pp. 187-191 CrossRefView Record in Scopus Kobayashi et al., 2000 K. Kobayashi, N. Takahashi, E. Jimi, N. Udagawa, M. Takami, S. Kotake, N. Nakagawa, M. Kinosaki, K. Yamaguchi, N. Shima, H. Yasuda, T. Morinaga, K. Higashio, T.J. Martin, T. Suda Tumor necrosis factor alpha stimulates osteoclast differentiation by a mechanism independent of the ODF/RANKL-RANK interaction J. Exp. Med., 191 (2) (2000), pp. 275-286 CrossRef Kobayashi et al., 2003 S. Kobayashi, H.E. Takahashi, A. Ito, N. Saito, M. Nawata, H. Horiuchi, H. Ohta, A. Ito, R. Iorio, N. Yamamoto, K. Takaoka Trabecular minimodeling in human iliac bone Bone, 32 (2) (2003), pp. 163-169 ArticleDownload PDFView Record in Scopus Kobayashi et al., 2012 M. Kobayashi, K. Watanabe, S. Yokoyama, C. Matsumoto, M. Hirata, T. Tominari, M. Inada, C. Miyaura Capsaicin, a TRPV1 Ligand, Suppresses Bone Resorption by Inhibiting the Prostaglandin E Production of Osteoblasts, and Attenuates the Inflammatory Bone Loss Induced by Lipopolysaccharide ISRN Pharmacol, 2012 (2012), p. 439860 View Record in Scopus Kochanowska et al., 2007 I. Kochanowska, S. Chaberek, A. Wojtowicz, B. Marczynski, K. Wlodarski, M. Dytko, K. Ostrowski Expression of genes for bone morphogenetic proteins BMP-2, BMP-4 and BMP-6 in various parts of the human skeleton BMC Musculoskelet. Disord., 8 (2007), p. 128 Kokabu et al., 2012 S. Kokabu, L. Gamer, K. Cox, J. Lowery, K. Tsuji, R. Raz, A. Economides, T. Katagiri, V. Rosen BMP3 suppresses osteoblast differentiation of bone marrow stromal cells via interaction with Acvr2b Mol. Endocrinol., 26 (1) (2012), pp. 87-94 CrossRefView Record in Scopus Kotecha and Lockwood, 2005 N. Kotecha, B. Lockwood Soy-relieving the symptoms of menopause and fighting osteoporosis Pharm. J., 275 (2005), p. 5 Krishnan et al., 2006 V. Krishnan, H.U. Bryant, O.A. Macdougald Regulation of bone mass by Wnt signaling J. Clin. Invest., 116 (5) (2006), pp. 1202-1209 CrossRefView Record in Scopus Kunnumakkara et al., 2007 A.B. Kunnumakkara, A.S. Nair, K.S. Ahn, M.K. Pandey, Z. Yi, M. Liu, B.B. Aggarwal Gossypin, a pentahydroxy glucosyl flavone, inhibits the transforming growth factor beta-activated kinase-1-mediated NF-kappaB activation pathway, leading to potentiation of apoptosis, suppression of invasion, and abrogation of osteoclastogenesis Blood, 109 (12) (2007), pp. 5112-5121 CrossRefView Record in Scopus Kunnumakkara et al., 2008 A.B. Kunnumakkara, H. Ichikawa, P. Anand, C.J. Mohankumar, P.S. Hema, M.S. Nair, B.B. Aggarwal Coronarin D, a labdane diterpene, inhibits both constitutive and inducible nuclear factor-kappa B pathway activation, leading to potentiation of apoptosis, inhibition of invasion, and suppression of osteoclastogenesis Mol. Cancer Ther., 7 (10) (2008), pp. 3306-3317 CrossRefView Record in Scopus Kushwaha et al., 2014 P. Kushwaha, V. Khedgikar, J. Gautam, P. Dixit, R. Chillara, A. Verma, R. Thakur, D.P. Mishra, D. Singh, R. Maurya, N. Chattopadhyay, P.R. Mishra, R. Trivedi A novel therapeutic approach with Caviunin-based isoflavonoid that en routes bone marrow cells to bone formation via BMP2/Wnt-beta-catenin signaling Cell Death Dis., 5 (2014), p. e1422 CrossRef Kwon et al., 2016 S.M. Kwon, S. Kim, N.J. Song, S.H. Chang, Y.J. Hwang, D.K. Yang, J.W. Hong, W.J. Park, K.W. Park Antiadipogenic and proosteogenic effects of luteolin, a major dietary flavone, are mediated by the induction of DnaJ (Hsp40) Homolog, Subfamily B, Member 1 J. Nutr. Biochem., 30 (2016), pp. 24-32 ArticleDownload PDFView Record in Scopus Lai et al., 2005 K.-A. Lai, W.-J. Shen, C.-Y. Yang, C.-J. Shao, J.-T. Hsu, R.-M. Lin The use of alendronate to prevent early collapse of the femoral head in patients with nontraumatic osteonecrosis: a randomized clinical study JBJS, 87 (10) (2005), pp. 2155-2159 CrossRefView Record in Scopus Laine et al., 2011 C.M. Laine, B.D. Chung, M. Susic, T. Prescott, O. Semler, T. Fiskerstrand, P. D'Eufemia, M. Castori, M. Pekkinen, E. Sochett, W.G. Cole, C. Netzer, O. Makitie Novel mutations affecting LRP5 splicing in patients with osteoporosis-pseudoglioma syndrome (OPPG) Eur. J. Hum. Genet., 19 (8) (2011), pp. 875-881 CrossRefView Record in Scopus Lamb et al., 2011 J.J. Lamb, M.F. Holick, R.H. Lerman, V.R. Konda, D.M. Minich, A. Desai, T.C. Chen, M. Austin, J. Kornberg, J.L. Chang, A. Hsi, J.S. Bland, M.L. Tripp Nutritional supplementation of hop rho iso-alpha acids, berberine, vitamin D(3), and vitamin K(1) produces a favorable bone biomarker profile supporting healthy bone metabolism in postmenopausal women with metabolic syndrome Nutr. Res., 31 (5) (2011), pp. 347-355 ArticleDownload PDFView Record in Scopus Langdahl et al., 2017 B.L. Langdahl, C. Libanati, D.B. Crittenden, M.A. Bolognese, J.P. Brown, N.S. Daizadeh, E. Dokoupilova, K. Engelke, J.S. Finkelstein, H.K. Genant, S. Goemaere, L. Hyldstrup, E. Jodar-Gimeno, T.M. Keaveny, D. Kendler, P. Lakatos, J. Maddox, J. Malouf, F.E. Massari, J.F. Molina, M.R. Ulla, A. Grauer Romosozumab (sclerostin monoclonal antibody) versus teriparatide in postmenopausal women with osteoporosis transitioning from oral bisphosphonate therapy: a randomised, open-label, phase 3 trial Lancet, 390 (10102) (2017), pp. 1585-1594 ArticleDownload PDFView Record in Scopus Lange et al., 2017 U. Lange, K. Classen, U. Muller-Ladner, M. Richter Weekly oral bisphosphonates over 2 years prevent bone loss in cardiac transplant patients Clin. Transpl., 31 (11) (2017) Lappe et al., 2013 J. Lappe, I. Kunz, I. Bendik, K. Prudence, P. Weber, R. Recker, R.P. Heaney Effect of a combination of genistein, polyunsaturated fatty acids and vitamins D3 and K1 on bone mineral density in postmenopausal women: a randomized, placebo-controlled, double-blind pilot study Eur. J. Nutr., 52 (1) (2013), pp. 203-215 CrossRefView Record in Scopus Lee et al., 2003 M.H. Lee, Y.J. Kim, H.J. Kim, H.D. Park, A.R. Kang, H.M. Kyung, J.H. Sung, J.M. Wozney, H.J. Kim, H.M. Ryoo BMP-2-induced Runx2 expression is mediated by Dlx5, and TGF-beta 1 opposes the BMP-2-induced osteoblast differentiation by suppression of Dlx5 expression J. Biol. Chem., 278 (36) (2003), pp. 34387-34394 CrossRefView Record in Scopus Lee et al., 2008 H.W. Lee, J.H. Suh, H.N. Kim, A.Y. Kim, S.Y. Park, C.S. Shin, J.Y. Choi, J.B. Kim Berberine promotes osteoblast differentiation by Runx2 activation with p38 MAPK J. Bone Miner. Res., 23 (8) (2008), pp. 1227-1237 CrossRef Lee et al., 2009 J.W. Lee, J.Y. Ahn, S. Hasegawa, B.Y. Cha, T. Yonezawa, K. Nagai, H.J. Seo, W.B. Jeon, J.T. Woo Inhibitory effect of luteolin on osteoclast differentiation and function Cytotechnology, 61 (3) (2009), pp. 125-134 ArticleDownload PDFCrossRefView Record in Scopus Lee et al., 2015 J.W. Lee, M. Asai, S.K. Jeon, T. Iimura, T. Yonezawa, B.Y. Cha, J.T. Woo, A. Yamaguchi Rosmarinic acid exerts an antiosteoporotic effect in the RANKL-induced mouse model of bone loss by promotion of osteoblastic differentiation and inhibition of osteoclastic differentiation Mol. Nutr. Food Res., 59 (3) (2015), pp. 386-400 CrossRefView Record in Scopus Lee et al., 2017 A.M. Lee, T. Shandala, P.P. Soo, Y.W. Su, T.J. King, K.M. Chen, P.R. Howe, C.J. Xian Effects of Resveratrol Supplementation on Methotrexate Chemotherapy-Induced Bone Loss Nutrients, 9 (3) (2017) Leotoing et al., 2013 L. Leotoing, F. Wauquier, J. Guicheux, E. Miot-Noirault, Y. Wittrant, V. Coxam The polyphenol fisetin protects bone by repressing NF-kappaB and MKP-1-dependent signaling pathways in osteoclasts PLoS One, 8 (7) (2013), Article e68388 CrossRef Leotoing et al., 2014 L. Leotoing, M.J. Davicco, P. Lebecque, Y. Wittrant, V. Coxam The flavonoid fisetin promotes osteoblasts differentiation through Runx2 transcriptional activity Mol. Nutr. Food Res., 58 (6) (2014), pp. 1239-1248 CrossRefView Record in Scopus Li and Yu, 2003 B. Li, S. Yu Genistein prevents bone resorption diseases by inhibiting bone resorption and stimulating bone formation Biol. Pharm. Bull., 26 (6) (2003), pp. 780-786 CrossRefView Record in Scopus Li et al., 2012 Z. Li, J. Xiao, X. Wu, W. Li, Z. Yang, J. Xie, L. Xu, X. Cai, Z. Lin, W. Guo, J. Luo, M. Liu Plumbagin inhibits breast tumor bone metastasis and osteolysis by modulating the tumor-bone microenvironment Curr. Mol. Med., 12 (8) (2012), pp. 967-981 CrossRefView Record in Scopus Liang et al., 2012 H. Liang, F. Yu, Z. Tong, W. Zeng Lycopene effects on serum mineral elements and bone strength in rats Molecules, 17 (6) (2012), pp. 7093-7102 CrossRefView Record in Scopus Liao et al., 2014 M.H. Liao, Y.T. Tai, Y.G. Cherng, S.H. Liu, Y.A. Chang, P.I. Lin, R.M. Chen Genistein induces oestrogen receptor-alpha gene expression in osteoblasts through the activation of mitogen-activated protein kinases/NF-kappaB/activator protein-1 and promotes cell mineralisation Br. J. Nutr., 111 (1) (2014), pp. 55-63 CrossRefView Record in Scopus Lindsay et al., 1999 R. Lindsay, F. Cosman, R.A. Lobo, B.W. Walsh, S.T. Harris, J.E. Reagan, C.L. Liss, M.E. Melton, C.A. Byrnes Addition of alendronate to ongoing hormone replacement therapy in the treatment of osteoporosis: a randomized, controlled clinical trial J. Clin. Endocrinol. Metab., 84 (9) (1999), pp. 3076-3081 CrossRefView Record in Scopus Lisabeth et al., 2013 E.M. Lisabeth, G. Falivelli, E.B. Pasquale Eph receptor signaling and ephrins Cold Spring Harb. Perspect. Biol., 5 (9) (2013) Liu et al., 2014 P. Liu, D.Q. Yang, F. Xie, B. Zhou, M. Liu Effect of calcitonin on anastrozole-induced bone pain during aromatase inhibitor therapy for breast cancer Genet. Mol. Res., 13 (3) (2014), pp. 5285-5291 CrossRefView Record in Scopus Liu et al., 2016a Y.Q. Liu, X.F. Han, J.X. Bo, H.P. Ma Wedelolactone Enhances Osteoblastogenesis but Inhibits Osteoclastogenesis through Sema3A/NRP1/PlexinA1 Pathway Front. Pharmacol., 7 (2016), p. 375 CrossRefView Record in Scopus Liu et al., 2016b Y.Q. Liu, Z.L. Hong, L.B. Zhan, H.Y. Chu, X.Z. Zhang, G.H. Li Wedelolactone enhances osteoblastogenesis by regulating Wnt/beta-catenin signaling pathway but suppresses osteoclastogenesis by NF-kappaB/c-fos/NFATc1 pathway Sci. Rep., 6 (2016), Article 32260 Looker et al., 2017 A.C. Looker, I.N. S, B. Fan, A.S. J FRAX-based estimates of 10-year probability of hip and major osteoporotic fracture among adults aged 40 and over: United States, 2013 and 2014 National health statistics reports, 103 (2017), pp. 1-16 View Record in Scopus Lu et al., 2016 H. Lu, R.E. Champlin, U. Popat, X. Pundole, C.P. Escalante, X. Wang, W. Qiao, W.A. Murphy, R.F. Gagel Ibandronate for the prevention of bone loss after allogeneic stem cell transplantation for hematologic malignancies: a randomized-controlled trial BoneKEy reports, 5 (2016), p. 843 View Record in Scopus Lu et al., 2017 C. Lu, Y. Chen, B. Zhang, Y. Chen, F. Bai, D. Chen Response to teriparatide in Chinese patients with established osteoporosis: osteocalcin and lumbar spine bone-mineral density changes from teriparatide Phase III study Clin. Interv. Aging, 12 (2017), pp. 1717-1723 CrossRefView Record in Scopus Ma et al., 2015 J. Ma, Y. Ma, X. Liu, S. Chen, C. Liu, A. Qin, S. Fan Gambogic acid inhibits osteoclast formation and ovariectomy-induced osteoporosis by suppressing the JNK, p38 and Akt signalling pathways Biochem. J., 469 (3) (2015), pp. 399-408 CrossRefView Record in Scopus Mackinnon et al., 2011 E.S. Mackinnon, A.V. Rao, R.G. Josse, L.G. Rao Supplementation with the antioxidant lycopene significantly decreases oxidative stress parameters and the bone resorption marker N-telopeptide of type I collagen in postmenopausal women Osteoporos. Int., 22 (4) (2011), pp. 1091-1101 CrossRefView Record in Scopus Mandema et al., 2014 J.W. Mandema, J. Zheng, C. Libanati, J.J. Perez Ruixo Time course of bone mineral density changes with denosumab compared with other drugs in postmenopausal osteoporosis: a dose-response-based meta-analysis J. Clin. Endocrinol. Metab., 99 (10) (2014), pp. 3746-3755 CrossRefView Record in Scopus Manna et al., 2000 S.K. Manna, A. Mukhopadhyay, B.B. Aggarwal Resveratrol suppresses TNF-induced activation of nuclear transcription factors NF-kappa B, activator protein-1, and apoptosis: potential role of reactive oxygen intermediates and lipid peroxidation J. Immunol., 164 (12) (2000), pp. 6509-6519 CrossRefView Record in Scopus Maricic, 2007 M. Maricic New and emerging treatments for osteoporosis Curr. Opin. Rheumatol., 19 (4) (2007), pp. 364-369 CrossRefView Record in Scopus Marzia et al., 2000 M. Marzia, N.A. Sims, S. Voit, S. Migliaccio, A. Taranta, S. Bernardini, T. Faraggiana, T. Yoneda, G.R. Mundy, B.F. Boyce, R. Baron, A. Teti Decreased c-Src expression enhances osteoblast differentiation and bone formation J. Cell Biol., 151 (2) (2000), pp. 311-320 CrossRefView Record in Scopus Masuhara et al., 2016 M. Masuhara, T. Tsukahara, K. Tomita, M. Furukawa, S. Miyawaki, T. Sato A relation between osteoclastogenesis inhibition and membrane-type estrogen receptor GPR30 Biochem Biophys Rep, 8 (2016), pp. 389-394 ArticleDownload PDFView Record in Scopus Matsubara et al., 2008 T. Matsubara, K. Kida, A. Yamaguchi, K. Hata, F. Ichida, H. Meguro, H. Aburatani, R. Nishimura, T. Yoneda BMP2 regulates Osterix through Msx2 and Runx2 during osteoblast differentiation J. Biol. Chem., 283 (43) (2008), pp. 29119-29125 CrossRefView Record in Scopus Matsuda et al., 2018 Y. Matsuda, T. Minagawa, T. Okui, K. Yamazaki Resveratrol suppresses the alveolar bone resorption induced by artificial trauma from occlusion in mice Oral Dis., 24 (3) (2018), pp. 412-421 View Record in Scopus McLean, 2009 R.R. McLean Proinflammatory cytokines and osteoporosis Curr Osteoporos Rep, 7 (4) (2009), pp. 134-139 CrossRefView Record in Scopus Meier et al., 2017 C. Meier, B. Uebelhart, B. Aubry-Rozier, M. Birkhauser, H.A. Bischoff-Ferrari, D. Frey, R.W. Kressig, O. Lamy, K. Lippuner, P. Stute, N. Suhm, S. Ferrari Osteoporosis drug treatment: duration and management after discontinuation. A position statement from the SVGO/ASCO Swiss Med. Wkly., 147 (2017), Article w14484 von Metzler et al., 2009 I. von Metzler, H. Krebbel, U. Kuckelkorn, U. Heider, C. Jakob, M. Kaiser, C. Fleissner, E. Terpos, O. Sezer Curcumin diminishes human osteoclastogenesis by inhibition of the signalosome-associated I kappaB kinase J. Cancer Res. Clin. Oncol., 135 (2) (2009), pp. 173-179 CrossRefView Record in Scopus Ming et al., 2013 L.G. Ming, K.M. Chen, C.J. Xian Functions and action mechanisms of flavonoids genistein and icariin in regulating bone remodeling J. Cell. Physiol., 228 (3) (2013), pp. 513-521 CrossRefView Record in Scopus Miyazaki et al., 2004 T. Miyazaki, A. Sanjay, L. Neff, S. Tanaka, W.C. Horne, R. Baron Src kinase activity is essential for osteoclast function J. Biol. Chem., 279 (17) (2004), pp. 17660-17666 CrossRefView Record in Scopus Miyazono et al., 2000 K. Miyazono, P. ten Dijke, C.H. Heldin TGF-beta signaling by Smad proteins Adv. Immunol., 75 (2000), pp. 115-157 ArticleDownload PDFView Record in Scopus Mobasheri and Shakibaei, 2013 A. Mobasheri, M. Shakibaei Osteogenic effects of resveratrol in vitro: potential for the prevention and treatment of osteoporosis Ann. N. Y. Acad. Sci., 1290 (2013), pp. 59-66 CrossRefView Record in Scopus Mohd Fozi et al., 2013 N.F. Mohd Fozi, M. Mazlan, A.N. Shuid, M. Isa Naina Milk thistle: a future potential anti-osteoporotic and fracture healing agent Curr. Drug Targets, 14 (14) (2013), pp. 1659-1666 CrossRef Monda et al., 2017 V. Monda, G.A. Lupoli, G. Messina, R. Peluso, A. Panico, I. Villano, M. Salerno, F. Sessa, F. Marciello, F. Moscatelli, A. Valenzano, L. Molino, R. Lupoli, F. Fonderico, A. Tortora, A. Pisano, M. Ruberto, M. Gabriella, G. Cavaliere, G. Trinchese, M.P. Mollica, L. Cipolloni, G. Cibelli, M. Monda, G. Lupoli, A. Messina Improvement of Bone Physiology and Life Quality Due to Association of Risedronate and Anastrozole Front. Pharmacol., 8 (2017), p. 632 Morabito et al., 2002 N. Morabito, A. Crisafulli, C. Vergara, A. Gaudio, A. Lasco, N. Frisina, R. D'Anna, F. Corrado, M.A. Pizzoleo, M. Cincotta, D. Altavilla, R. Ientile, F. Squadrito Effects of genistein and hormone-replacement therapy on bone loss in early postmenopausal women: a randomized double-blind placebo-controlled study J. Bone Miner. Res., 17 (10) (2002), pp. 1904-1912 CrossRefView Record in Scopus Morley et al., 2001 P. Morley, J.F. Whitfield, G.E. Willick Parathyroid hormone: an anabolic treatment for osteoporosis Curr. Pharm. Des., 7 (8) (2001), pp. 671-687 CrossRefView Record in Scopus Mundy and Edwards, 2008 G.R. Mundy, J.R. Edwards PTH-related peptide (PTHrP) in hypercalcemia J. Am. Soc. Nephrol., 19 (4) (2008), pp. 672-675 CrossRefView Record in Scopus Nakagawa et al., 2014 Y. Nakagawa, S. Mukai, S. Yamada, M. Matsuoka, E. Tarumi, T. Hashimoto, C. Tamura, A. Imaizumi, J. Nishihira, T. Nakamura Short-term effects of highly-bioavailable curcumin for treating knee osteoarthritis: a randomized, double-blind, placebo-controlled prospective study J. Orthop. Sci., 19 (6) (2014), pp. 933-939 ArticleDownload PDFCrossRefView Record in Scopus Nakamura et al., 2017 Y. Nakamura, T. Suzuki, H. Kato Denosumab significantly improves bone mineral density with or without bisphosphonate pre-treatment in osteoporosis with rheumatoid arthritis: Denosumab improves bone mineral density in osteoporosis with rheumatoid arthritis Arch. Osteoporos., 12 (1) (2017), p. 80 CrossRefView Record in Scopus Nakatsukasa et al., 2017 K. Nakatsukasa, H. Koyama, Y. Ouchi, K. Sakaguchi, Y. Fujita, T. Matsuda, M. Kato, E. Konishi, T. Taguchi Effect of denosumab administration on low bone mineral density (T-score -1.0 to -2.5) in postmenopausal Japanese women receiving adjuvant aromatase inhibitors for non-metastatic breast cancer J. Bone Miner. Metab. (2017), 10.1007/s00774-017-0884-x Niziolek et al., 2015 P.J. Niziolek, W. Bullock, M.L. Warman, A.G. Robling Missense Mutations in LRP5 Associated with High Bone Mass Protect the Mouse Skeleton from Disuse- and Ovariectomy-Induced Osteopenia PLoS One, 10 (11) (2015), Article e0140775 CrossRef Novack, 2011 D.V. Novack Role of NF-kappaB in the skeleton Cell Res., 21 (1) (2011), pp. 169-182 CrossRefView Record in Scopus Oh et al., 2008 S. Oh, T.W. Kyung, H.S. Choi Curcumin inhibits osteoclastogenesis by decreasing receptor activator of nuclear factor-kappaB ligand (RANKL) in bone marrow stromal cells Mol. Cell, 26 (5) (2008), pp. 486-489 View Record in Scopus Okamoto et al., 2014 M. Okamoto, N. Udagawa, S. Uehara, K. Maeda, T. Yamashita, Y. Nakamichi, H. Kato, N. Saito, Y. Minami, N. Takahashi, Y. Kobayashi Noncanonical Wnt5a enhances Wnt/beta-catenin signaling during osteoblastogenesis Sci. Rep., 4 (2014), p. 4493 Omori et al., 2015 A. Omori, Y. Yoshimura, Y. Deyama, K. Suzuki Rosmarinic acid and arbutin suppress osteoclast differentiation by inhibiting superoxide and NFATc1 downregulation in RAW 264.7 cells Biomed Rep, 3 (4) (2015), pp. 483-490 CrossRefView Record in Scopus Onodera et al., 2017 S. Onodera, A. Saito, D. Hasegawa, N. Morita, K. Watanabe, T. Nomura, T. Shibahara, S. Ohba, A. Yamaguchi, T. Azuma Multi-layered mutation in hedgehog-related genes in Gorlin syndrome may affect the phenotype PLoS One, 12 (9) (2017), Article e0184702 CrossRef Ornitz, 2005 D.M. Ornitz FGF signaling in the developing endochondral skeleton Cytokine Growth Factor Rev., 16 (2) (2005), pp. 205-213 ArticleDownload PDFView Record in Scopus Ornitz and Marie, 2015 D.M. Ornitz, P.J. Marie Fibroblast growth factor signaling in skeletal development and disease Genes Dev., 29 (14) (2015), pp. 1463-1486 CrossRefView Record in Scopus Pan et al., 2013 A. Pan, L. Chang, A. Nguyen, A.W. James A review of hedgehog signaling in cranial bone development Front. Physiol., 4 (2013), p. 61 View Record in Scopus Panahi et al., 2014 Y. Panahi, A.R. Rahimnia, M. Sharafi, G. Alishiri, A. Saburi, A. Sahebkar Curcuminoid treatment for knee osteoarthritis: a randomized double-blind placebo-controlled trial Phytother. Res., 28 (11) (2014), pp. 1625-1631 CrossRefView Record in Scopus Pandey et al., 2014 M.K. Pandey, V.P. Kale, C. Song, S.S. Sung, A.K. Sharma, G. Talamo, S. Dovat, S.G. Amin Gambogic acid inhibits multiple myeloma mediated osteoclastogenesis through suppression of chemokine receptor CXCR4 signaling pathways Exp. Hematol., 42 (10) (2014), pp. 883-896 ArticleDownload PDFView Record in Scopus Pangrazio et al., 2012 A. Pangrazio, B. Cassani, M.M. Guerrini, J.C. Crockett, V. Marrella, L. Zammataro, D. Strina, A. Schulz, C. Schlack, U. Kornak, D.J. Mellis, A. Duthie, M.H. Helfrich, A. Durandy, D. Moshous, A. Vellodi, R. Chiesa, P. Veys, N. Lo Iacono, P. Vezzoni, A. Fischer, A. Villa, C. Sobacchi RANK-dependent autosomal recessive osteopetrosis: characterization of five new cases with novel mutations J. Bone Miner. Res., 27 (2) (2012), pp. 342-351 CrossRefView Record in Scopus Park et al., 2010 O.J. Park, H.J. Kim, K.M. Woo, J.H. Baek, H.M. Ryoo FGF2-activated ERK mitogen-activated protein kinase enhances Runx2 acetylation and stabilization J. Biol. Chem., 285 (6) (2010), pp. 3568-3574 CrossRefView Record in Scopus Park et al., 2014 S.Y. Park, H.J. Kim, K.R. Kim, S.K. Lee, C.K. Lee, K.K. Park, W.Y. Chung Betulinic acid, a bioactive pentacyclic triterpenoid, inhibits skeletal-related events induced by breast cancer bone metastases and treatment Toxicol. Appl. Pharmacol., 275 (2) (2014), pp. 152-162 ArticleDownload PDFView Record in Scopus Pasquale, 2008 E.B. Pasquale Eph-ephrin bidirectional signaling in physiology and disease Cell, 133 (1) (2008), pp. 38-52 ArticleDownload PDFView Record in Scopus Pettit et al., 2006 A.R. Pettit, N.C. Walsh, C. Manning, S.R. Goldring, E.M. Gravallese RANKL protein is expressed at the pannus-bone interface at sites of articular bone erosion in rheumatoid arthritis Rheumatology (Oxford), 45 (9) (2006), pp. 1068-1076 CrossRefView Record in Scopus Phimphilai et al., 2006 M. Phimphilai, Z. Zhao, H. Boules, H. Roca, R.T. Franceschi BMP signaling is required for RUNX2-dependent induction of the osteoblast phenotype J. Bone Miner. Res., 21 (4) (2006), pp. 637-646 CrossRefView Record in Scopus Qiao et al., 1997 J.H. Qiao, J. Tripathi, N.K. Mishra, Y. Cai, S. Tripathi, X.P. Wang, S. Imes, M.C. Fishbein, S.K. Clinton, P. Libby, A.J. Lusis, T.B. Rajavashisth Role of macrophage colony-stimulating factor in atherosclerosis: studies of osteopetrotic mice Am. J. Pathol., 150 (5) (1997), pp. 1687-1699 View Record in Scopus Rachner et al., 2011 T.D. Rachner, S. Khosla, L.C. Hofbauer Osteoporosis: now and the future Lancet, 377 (9773) (2011), pp. 1276-1287 ArticleDownload PDFView Record in Scopus Rahimnia et al., 2015 A.R. Rahimnia, Y. Panahi, G. Alishiri, M. Sharafi, A. Sahebkar Impact of Supplementation with Curcuminoids on Systemic Inflammation in Patients with Knee Osteoarthritis: Findings from a Randomized Double-Blind Placebo-Controlled Trial Drug Res (Stuttg), 65 (10) (2015), pp. 521-525 Rahman et al., 2015 M.S. Rahman, N. Akhtar, H.M. Jamil, R.S. Banik, S.M. Asaduzzaman TGF-beta/BMP signaling and other molecular events: regulation of osteoblastogenesis and bone formation Bone Res, 3 (2015), p. 15005 Rantlha et al., 2017 M. Rantlha, T. Sagar, M.C. Kruger, M. Coetzee, V. Deepak Ellagic acid inhibits RANKL-induced osteoclast differentiation by suppressing the p38 MAP kinase pathway Arch. Pharm. Res., 40 (1) (2017), pp. 79-87 CrossRefView Record in Scopus Regard et al., 2012 J.B. Regard, Z. Zhong, B.O. Williams, Y. Yang Wnt signaling in bone development and disease: making stronger bone with Wnts Cold Spring Harb. Perspect. Biol., 4 (12) (2012) Reginster et al., 2017 J.Y. Reginster, N.M. Al Daghri, O. Bruyere Abaloparatide Comparator Trial In Vertebral Endpoints (ACTIVE) confirms that abaloparatide is a valuable addition to the armamentarium against osteoporosis Expert. Opin. Pharmacother., 18 (17) (2017), pp. 1811-1813 CrossRefView Record in Scopus Ren and Zhou, 2015 Y.Q. Ren, Y.B. Zhou Inhibition of andrographolide in RAW 264.7 murine macrophage osteoclastogenesis by downregulating the nuclear factor-kappaB signaling pathway Genet. Mol. Res., 14 (4) (2015), pp. 15955-15961 CrossRefView Record in Scopus Reuter et al., 2010 S. Reuter, S. Prasad, K. Phromnoi, R. Kannappan, V.R. Yadav, B.B. Aggarwal Embelin suppresses osteoclastogenesis induced by receptor activator of NF-kappaB ligand and tumor cells in vitro through inhibition of the NF-kappaB cell signaling pathway Mol. Cancer Res., 8 (10) (2010), pp. 1425-1436 CrossRefView Record in Scopus Reuter et al., 2012 S. Reuter, S.C. Gupta, K. Phromnoi, B.B. Aggarwal Thiocolchicoside suppresses osteoclastogenesis induced by RANKL and cancer cells through inhibition of inflammatory pathways: a new use for an old drug Br. J. Pharmacol., 165 (7) (2012), pp. 2127-2139 CrossRefView Record in Scopus Riva et al., 2017a A. Riva, F. Franceschi, S. Togni, R. Eggenhoffner, L. Giacomelli Health benefits of curcumin and curcumin phytosome in bone density disorders JSM Bone Marrow Res, 1 (2) (2017), pp. 1006-1009 Riva et al., 2017b A. Riva, S. Togni, L. Giacomelli, F. Franceschi, R. Eggenhoffner, B. Feragalli, G. Belcaro, M. Cacchio, H. Shu, M. Dugall Effects of a curcumin-based supplementation in asymptomatic subjects with low bone density: a preliminary 24-week supplement study Eur Rev Med Pharmacol Sci, 21 (7) (2017), pp. 1684-1689 View Record in Scopus Roodman, 1999 G.D. Roodman Cell biology of the osteoclast Exp. Hematol., 27 (8) (1999), pp. 1229-1241 ArticleDownload PDFView Record in Scopus Roux et al., 2002 S. Roux, L. Amazit, G. Meduri, A. Guiochon-Mantel, E. Milgrom, X. Mariette RANK (receptor activator of nuclear factor kappa B) and RANK ligand are expressed in giant cell tumors of bone Am. J. Clin. Pathol., 117 (2) (2002), pp. 210-216 CrossRefView Record in Scopus Ruocco et al., 2005 M.G. Ruocco, S. Maeda, J.M. Park, T. Lawrence, L.C. Hsu, Y. Cao, G. Schett, E.F. Wagner, M. Karin I{kappa}B kinase (IKK){beta}, but not IKK{alpha}, is a critical mediator of osteoclast survival and is required for inflammation-induced bone loss J. Exp. Med., 201 (10) (2005), pp. 1677-1687 CrossRefView Record in Scopus Ryoo et al., 1997 H.M. Ryoo, H.M. Hoffmann, T. Beumer, B. Frenkel, D.A. Towler, G.S. Stein, J.L. Stein, A.J. van Wijnen, J.B. Lian Stage-specific expression of Dlx-5 during osteoblast differentiation: involvement in regulation of osteocalcin gene expression Mol. Endocrinol., 11 (11) (1997), pp. 1681-1694 CrossRefView Record in Scopus Sakai et al., 2012 E. Sakai, M. Shimada-Sugawara, K. Nishishita, Y. Fukuma, M. Naito, K. Okamoto, K. Nakayama, T. Tsukuba Suppression of RANKL-dependent heme oxygenase-1 is required for high mobility group box 1 release and osteoclastogenesis J. Cell. Biochem., 113 (2) (2012), pp. 486-498 CrossRefView Record in Scopus Sakai et al., 2013 E. Sakai, M. Shimada-Sugawara, Y. Yamaguchi, H. Sakamoto, R. Fumimoto, Y. Fukuma, K. Nishishita, K. Okamoto, T. Tsukuba Fisetin inhibits osteoclastogenesis through prevention of RANKL-induced ROS production by Nrf2-mediated up-regulation of phase II antioxidant enzymes J. Pharmacol. Sci., 121 (4) (2013), pp. 288-298 CrossRefView Record in Scopus Sandur et al., 2007 S.K. Sandur, K.S. Ahn, H. Ichikawa, G. Sethi, S. Shishodia, R.A. Newman, B.B. Aggarwal Zyflamend, a polyherbal preparation, inhibits invasion, suppresses osteoclastogenesis, and potentiates apoptosis through down-regulation of NF-kappa B activation and NF-kappa B-regulated gene products Nutr. Cancer, 57 (1) (2007), pp. 78-87 CrossRefView Record in Scopus Sapir-Koren and Livshits, 2017 R. Sapir-Koren, G. Livshits Postmenopausal osteoporosis in rheumatoid arthritis: The estrogen deficiency-immune mechanisms link Bone, 103 (2017), pp. 102-115 ArticleDownload PDFView Record in Scopus Schett, 2011 G. Schett Effects of inflammatory and anti-inflammatory cytokines on the bone Eur. J. Clin. Investig., 41 (12) (2011), pp. 1361-1366 CrossRefView Record in Scopus Sethi and Aggarwal, 2007 G. Sethi, B.B. Aggarwal Mending the bones with natural products Chem. Biol., 14 (7) (2007), pp. 738-740 ArticleDownload PDFView Record in Scopus Shakibaei et al., 2011 M. Shakibaei, C. Buhrmann, A. Mobasheri Resveratrol-mediated SIRT-1 interactions with p300 modulate receptor activator of NF-kappaB ligand (RANKL) activation of NF-kappaB signaling and inhibit osteoclastogenesis in bone-derived cells J. Biol. Chem., 286 (13) (2011), pp. 11492-11505 CrossRefView Record in Scopus Shang et al., 2016 W. Shang, L.J. Zhao, X.L. Dong, Z.M. Zhao, J. Li, B.B. Zhang, H. Cai Curcumin inhibits osteoclastogenic potential in PBMCs from rheumatoid arthritis patients via the suppression of MAPK/RANK/c-Fos/NFATc1 signaling pathways Mol. Med. Rep., 14 (4) (2016), pp. 3620-3626 CrossRefView Record in Scopus Sharma and Pradeep, 2012 A. Sharma, A.R. Pradeep Clinical efficacy of 1% alendronate gel as a local drug delivery system in the treatment of chronic periodontitis: a randomized, controlled clinical trial J. Periodontol., 83 (1) (2012), pp. 11-18 CrossRefView Record in Scopus Shen et al., 2009 C.L. Shen, J.K. Yeh, J.J. Cao, J.S. Wang Green tea and bone metabolism Nutr. Res., 29 (7) (2009), pp. 437-456 ArticleDownload PDFView Record in Scopus Shen et al., 2014 J. Shen, S. Li, D. Chen TGF-beta signaling and the development of osteoarthritis Bone Res, 2 (2014) Shimizu et al., 2017 T. Shimizu, T. Tanaka, T. Kobayashi, I. Kudo, M. Nakatsugawa, A. Takakura, R. Takao-Kawabata, T. Ishizuya Sequential treatment with zoledronic acid followed by teriparatide or vice versa increases bone mineral density and bone strength in ovariectomized rats Bone reports, 7 (2017), pp. 70-82 ArticleDownload PDFView Record in Scopus Shin et al., 2012 D.K. Shin, M.H. Kim, S.H. Lee, T.H. Kim, S.Y. Kim Inhibitory effects of luteolin on titanium particle-induced osteolysis in a mouse model Acta Biomater., 8 (9) (2012), pp. 3524-3531 ArticleDownload PDFView Record in Scopus Shin et al., 2017 K. Shin, S.H. Park, W. Park, H.J. Baek, Y.J. Lee, S.W. Kang, J.Y. Choe, W.H. Yoo, Y.B. Park, J.S. Song, S.G. Lee, B. Yoo, D.H. Yoo, Y.W. Song Monthly Oral Ibandronate Reduces Bone Loss in Korean Women With Rheumatoid Arthritis and Osteopenia Receiving Long-term Glucocorticoids: A 48-week Double-blinded Randomized Placebo-controlled Investigator-initiated Trial Clin. Ther., 39 (2) (2017), pp. 268-278 (e262) CrossRef Shirley, 2017 M. Shirley Abaloparatide: First Global Approval Drugs, 77 (12) (2017), pp. 1363-1368 CrossRefView Record in Scopus Shishodia and Aggarwal, 2006a S. Shishodia, B.B. Aggarwal Diosgenin inhibits osteoclastogenesis, invasion, and proliferation through the downregulation of Akt, I kappa B kinase activation and NF-kappa B-regulated gene expression Oncogene, 25 (10) (2006), pp. 1463-1473 CrossRefView Record in Scopus Shishodia and Aggarwal, 2006b S. Shishodia, B.B. Aggarwal Resveratrol: A polyphenol for all seasons (2006) Shohrati et al., 2015 M. Shohrati, N. Bayat, A. Saburi, Z. Abbasi Effect of Nasal Calcitonin on the Health-Related Quality of Life in Postmenopause Women Affected With Low Bone Density Iran Red Crescent Med J, 17 (7) (2015), Article e6613 View Record in Scopus Singh and Aggarwal, 1995 S. Singh, B.B. Aggarwal Activation of transcription factor NF-kappa B is suppressed by curcumin (diferuloylmethane) [corrected] J. Biol. Chem., 270 (42) (1995), pp. 24995-25000 CrossRefView Record in Scopus Song et al., 2012 L. Song, M. Liu, N. Ono, F.R. Bringhurst, H.M. Kronenberg, J. Guo Loss of wnt/beta-catenin signaling causes cell fate shift of preosteoblasts from osteoblasts to adipocytes J. Bone Miner. Res., 27 (11) (2012), pp. 2344-2358 CrossRefView Record in Scopus Southmayd and De Souza, 2017 E.A. Southmayd, M.J. De Souza A summary of the influence of exogenous estrogen administration across the lifespan on the GH/IGF-1 axis and implications for bone health Growth hormone & IGF research: official journal of the Growth Hormone Research Society and the International IGF Research Society, 32 (2017), pp. 2-13 ArticleDownload PDFView Record in Scopus Sreekumar et al., 2017 V. Sreekumar, R. Aspera-Werz, S. Ehnert, J. Strobel, G. Tendulkar, D. Heid, A. Schreiner, C. Arnscheidt, A.K. Nussler Resveratrol protects primary cilia integrity of human mesenchymal stem cells from cigarette smoke to improve osteogenic differentiation in vitro Arch. Toxicol. (2017), 10.1007/s00204-017-2149-9 (In press) St-Jacques et al., 1999 B. St-Jacques, M. Hammerschmidt, A.P. McMahon Indian hedgehog signaling regulates proliferation and differentiation of chondrocytes and is essential for bone formation Genes Dev., 13 (16) (1999), pp. 2072-2086 CrossRefView Record in Scopus Streicher et al., 2017 C. Streicher, A. Heyny, O. Andrukhova, B. Haigl, S. Slavic, C. Schuler, K. Kollmann, I. Kantner, V. Sexl, M. Kleiter, L.C. Hofbauer, P.J. Kostenuik, R.G. Erben Estrogen Regulates Bone Turnover by Targeting RANKL Expression in Bone Lining Cells Sci. Rep., 7 (1) (2017), p. 6460 Su et al., 2014 N. Su, M. Jin, L. Chen Role of FGF/FGFR signaling in skeletal development and homeostasis: learning from mouse models Bone Res, 2 (2014), p. 14003 CrossRef Sung et al., 2009 B. Sung, A. Murakami, B.O. Oyajobi, B.B. Aggarwal Zerumbone abolishes RANKL-induced NF-kappaB activation, inhibits osteoclastogenesis, and suppresses human breast cancer-induced bone loss in athymic nude mice Cancer Res., 69 (4) (2009), pp. 1477-1484 CrossRefView Record in Scopus Sung et al., 2011 B. Sung, S.G. Cho, M. Liu, B.B. Aggarwal Butein, a tetrahydroxychalcone, suppresses cancer-induced osteoclastogenesis through inhibition of receptor activator of nuclear factor-kappaB ligand signaling Int. J. Cancer, 129 (9) (2011), pp. 2062-2072 CrossRefView Record in Scopus Sung et al., 2012 B. Sung, B. Oyajobi, B.B. Aggarwal Plumbagin inhibits osteoclastogenesis and reduces human breast cancer-induced osteolytic bone metastasis in mice through suppression of RANKL signaling Mol. Cancer Ther., 11 (2) (2012), pp. 350-359 CrossRefView Record in Scopus Sung et al., 2013 B. Sung, S. Prasad, V.R. Yadav, S.C. Gupta, S. Reuter, N. Yamamoto, A. Murakami, B.B. Aggarwal RANKL signaling and osteoclastogenesis is negatively regulated by cardamonin PLoS One, 8 (5) (2013), Article e64118 CrossRef Suzuki et al., 2018 T. Suzuki, F. Sukezaki, T. Shibuki, Y. Toyoshima, T. Nagai, K. Inagaki Teriparatide Administration Increases Periprosthetic Bone Mineral Density After Total Knee Arthroplasty: A Prospective Study J. Arthroplast., 33 (1) (2018), pp. 79-85 ArticleDownload PDFView Record in Scopus Takada et al., 2005 Y. Takada, M. Andreeff, B.B. Aggarwal Indole-3-carbinol suppresses NF-kappaB and IkappaBalpha kinase activation, causing inhibition of expression of NF-kappaB-regulated antiapoptotic and metastatic gene products and enhancement of apoptosis in myeloid and leukemia cells Blood, 106 (2) (2005), pp. 641-649 CrossRefView Record in Scopus Takada et al., 2006 Y. Takada, H. Ichikawa, V. Badmaev, B.B. Aggarwal Acetyl-11-keto-beta-boswellic acid potentiates apoptosis, inhibits invasion, and abolishes osteoclastogenesis by suppressing NF-kappa B and NF-kappa B-regulated gene expression J. Immunol., 176 (5) (2006), pp. 3127-3140 CrossRefView Record in Scopus Takagi et al., 2017 T. Takagi, H. Inoue, N. Takahashi, R. Katsumata-Tsuboi, M. Uehara Sulforaphane inhibits osteoclast differentiation by suppressing the cell-cell fusion molecules DC-STAMP and OC-STAMP Biochem. Biophys. Res. Commun., 483 (1) (2017), pp. 718-724 ArticleDownload PDFView Record in Scopus Takatsuka et al., 1998 H. Takatsuka, H. Umezu, G. Hasegawa, H. Usuda, Y. Ebe, M. Naito, L.D. Shultz Bone remodeling and macrophage differentiation in osteopetrosis (op) mutant mice defective in the production of macrophage colony-stimulating factor J. Submicrosc. Cytol. Pathol., 30 (2) (1998), pp. 239-247 View Record in Scopus Takyar et al., 2013 F.M. Takyar, S. Tonna, P.W. Ho, B. Crimeen-Irwin, E.K. Baker, T.J. Martin, N.A. Sims EphrinB2/EphB4 inhibition in the osteoblast lineage modifies the anabolic response to parathyroid hormone J. Bone Miner. Res., 28 (4) (2013), pp. 912-925 CrossRefView Record in Scopus Tao et al., 2016 K. Tao, D. Xiao, J. Weng, A. Xiong, B. Kang, H. Zeng Berberine promotes bone marrow-derived mesenchymal stem cells osteogenic differentiation via canonical Wnt/beta-catenin signaling pathway Toxicol. Lett., 240 (1) (2016), pp. 68-80 ArticleDownload PDFView Record in Scopus Teitelbaum, 2000 S.L. Teitelbaum Bone resorption by osteoclasts Science, 289 (5484) (2000), pp. 1504-1508 CrossRefView Record in Scopus Tella et al., 2017 S.H. Tella, A. Kommalapati, R. Correa Profile of Abaloparatide and Its Potential in the Treatment of Postmenopausal Osteoporosis Cureus, 9 (5) (2017), Article e1300 View Record in Scopus TenBroek et al., 2016 E.M. TenBroek, L. Yunker, M.F. Nies, A.M. Bendele Randomized controlled studies on the efficacy of antiarthritic agents in inhibiting cartilage degeneration and pain associated with progression of osteoarthritis in the rat Arthritis Res Ther, 18 (2016), p. 24 Teven et al., 2014 C.M. Teven, E.M. Farina, J. Rivas, R.R. Reid Fibroblast growth factor (FGF) signaling in development and skeletal diseases Genes Dis, 1 (2) (2014), pp. 199-213 ArticleDownload PDFView Record in Scopus Thomas, 2006 T. Thomas Intermittent parathyroid hormone therapy to increase bone formation Joint Bone Spine, 73 (3) (2006), pp. 262-269 ArticleDownload PDFView Record in Scopus Tolba et al., 2017 M.F. Tolba, A.T. El-Serafi, H.A. Omar Caffeic acid phenethyl ester protects against glucocorticoid-induced osteoporosis in vivo: Impact on oxidative stress and RANKL/OPG signals Toxicol. Appl. Pharmacol., 324 (2017), pp. 26-35 ArticleDownload PDFView Record in Scopus Tou, 2015 J.C. Tou Resveratrol supplementation affects bone acquisition and osteoporosis: Pre-clinical evidence toward translational diet therapy Biochim. Biophys. Acta, 1852 (6) (2015), pp. 1186-1194 ArticleDownload PDFView Record in Scopus Tsai et al., 2015 Y.M. Tsai, I.W. Chong, J.Y. Hung, W.A. Chang, P.L. Kuo, M.J. Tsai, Y.L. Hsu Syringetin suppresses osteoclastogenesis mediated by osteoblasts in human lung adenocarcinoma Oncol. Rep., 34 (2) (2015), pp. 617-626 CrossRefView Record in Scopus Tsuji et al., 2006 K. Tsuji, A. Bandyopadhyay, B.D. Harfe, K. Cox, S. Kakar, L. Gerstenfeld, T. Einhorn, C.J. Tabin, V. Rosen BMP2 activity, although dispensable for bone formation, is required for the initiation of fracture healing Nat. Genet., 38 (12) (2006), pp. 1424-1429 CrossRefView Record in Scopus Tsuji et al., 2009 M. Tsuji, H. Yamamoto, T. Sato, Y. Mizuha, Y. Kawai, Y. Taketani, S. Kato, J. Terao, T. Inakuma, E. Takeda Dietary quercetin inhibits bone loss without effect on the uterus in ovariectomized mice J. Bone Miner. Metab., 27 (6) (2009), pp. 673-681 CrossRefView Record in Scopus Tu et al., 2007 X. Tu, K.S. Joeng, K.I. Nakayama, K. Nakayama, J. Rajagopal, T.J. Carroll, A.P. McMahon, F. Long Noncanonical Wnt signaling through G protein-linked PKCdelta activation promotes bone formation Dev. Cell, 12 (1) (2007), pp. 113-127 ArticleDownload PDFView Record in Scopus Tyagi et al., 2016 A.K. Tyagi, S. Prasad, M. Majeed, B.B. Aggarwal Calebin A downregulates osteoclastogenesis through suppression of RANKL signalling Arch. Biochem. Biophys., 593 (2016), pp. 80-89 ArticleDownload PDFView Record in Scopus Udagawa et al., 1990 N. Udagawa, N. Takahashi, T. Akatsu, H. Tanaka, T. Sasaki, T. Nishihara, T. Koga, T.J. Martin, T. Suda Origin of osteoclasts: mature monocytes and macrophages are capable of differentiating into osteoclasts under a suitable microenvironment prepared by bone marrow-derived stromal cells Proc. Natl. Acad. Sci. U. S. A., 87 (18) (1990), pp. 7260-7264 CrossRefView Record in Scopus Umeda et al., 1996 S. Umeda, K. Takahashi, M. Naito, L.D. Shultz, K. Takagi Neonatal changes of osteoclasts in osteopetrosis (op/op) mice defective in production of functional macrophage colony-stimulating factor (M-CSF) protein and effects of M-CSF on osteoclast development and differentiation J. Submicrosc. Cytol. Pathol., 28 (1) (1996), pp. 13-26 View Record in Scopus Usami et al., 2016 Y. Usami, A.T. Gunawardena, M. Iwamoto, M. Enomoto-Iwamoto Wnt signaling in cartilage development and diseases: lessons from animal studies Lab. Investig., 96 (2) (2016), pp. 186-196 CrossRefView Record in Scopus Walsh and Choi, 2014 M.C. Walsh, Y. Choi Biology of the RANKL-RANK-OPG System in Immunity, Bone, and Beyond Front. Immunol., 5 (2014), p. 511 Wang et al., 2014a R.N. Wang, J. Green, Z. Wang, Y. Deng, M. Qiao, M. Peabody, Q. Zhang, J. Ye, Z. Yan, S. Denduluri, O. Idowu, M. Li, C. Shen, A. Hu, R.C. Haydon, R. Kang, J. Mok, M.J. Lee, H.L. Luu, L.L. Shi Bone Morphogenetic Protein (BMP) signaling in development and human diseases Genes Dis, 1 (1) (2014), pp. 87-105 ArticleDownload PDFView Record in Scopus Wang et al., 2014b X.C. Wang, N.J. Zhao, C. Guo, J.T. Chen, J.L. Song, L. Gao Quercetin reversed lipopolysaccharide-induced inhibition of osteoblast differentiation through the mitogenactivated protein kinase pathway in MC3T3-E1 cells Mol. Med. Rep., 10 (6) (2014), pp. 3320-3326 CrossRefView Record in Scopus Wang et al., 2014c Y. Wang, Y.P. Li, C. Paulson, J.Z. Shao, X. Zhang, M. Wu, W. Chen Wnt and the Wnt signaling pathway in bone development and disease Front Biosci (Landmark Ed), 19 (2014), pp. 379-407 CrossRefView Record in Scopus Wang et al., 2015 T. Wang, Q. Liu, L. Zhou, J.B. Yuan, X. Lin, R. Zeng, X. Liang, J. Zhao, J. Xu Andrographolide Inhibits Ovariectomy-Induced Bone Loss via the Suppression of RANKL Signaling Pathways Int. J. Mol. Sci., 16 (11) (2015), pp. 27470-27481 CrossRefView Record in Scopus Wang et al., 2016 N. Wang, F. Wang, Y. Gao, P. Yin, C. Pan, W. Liu, Z. Zhou, J. Wang Curcumin protects human adipose-derived mesenchymal stem cells against oxidative stress-induced inhibition of osteogenesis J. Pharmacol. Sci., 132 (3) (2016), pp. 192-200 ArticleDownload PDFView Record in Scopus Watanabe et al., 2016 R. Watanabe, N. Fujita, S. Takeda, Y. Sato, T. Kobayashi, M. Morita, T. Oike, K. Miyamoto, Y. Matsumoto, M. Matsumoto, M. Nakamura, T. Miyamoto Ibandronate concomitantly blocks immobilization-induced bone and muscle atrophy Biochem. Biophys. Res. Commun., 480 (4) (2016), pp. 662-668 ArticleDownload PDFView Record in Scopus Wattel et al., 2004 A. Wattel, S. Kamel, C. Prouillet, J.P. Petit, F. Lorget, E. Offord, M. Brazier Flavonoid quercetin decreases osteoclastic differentiation induced by RANKL via a mechanism involving NF kappa B and AP-1 J. Cell. Biochem., 92 (2) (2004), pp. 285-295 CrossRefView Record in Scopus Wei et al., 2005 S. Wei, H. Kitaura, P. Zhou, F.P. Ross, S.L. Teitelbaum IL-1 mediates TNF-induced osteoclastogenesis J. Clin. Invest., 115 (2) (2005), pp. 282-290 CrossRefView Record in Scopus Wei et al., 2009 P. Wei, L. Jiao, L.P. Qin, F. Yan, T. Han, Q.Y. Zhang Effects of berberine on differentiation and bone resorption of osteoclasts derived from rat bone marrow cells Zhong Xi Yi Jie He Xue Bao, 7 (4) (2009), pp. 342-348 CrossRefView Record in Scopus Wieland et al., 2004 I. Wieland, S. Jakubiczka, P. Muschke, M. Cohen, H. Thiele, K.L. Gerlach, R.H. Adams, P. Wieacker Mutations of the ephrin-B1 gene cause craniofrontonasal syndrome Am. J. Hum. Genet., 74 (6) (2004), pp. 1209-1215 ArticleDownload PDFCrossRefView Record in Scopus Wozney, 1992 J.M. Wozney The bone morphogenetic protein family and osteogenesis Mol. Reprod. Dev., 32 (2) (1992), pp. 160-167 CrossRefView Record in Scopus Wu et al., 2012 X. Wu, Z. Li, Z. Yang, C. Zheng, J. Jing, Y. Chen, X. Ye, X. Lian, W. Qiu, F. Yang, J. Tang, J. Xiao, M. Liu, J. Luo Caffeic acid 3,4-dihydroxy-phenethyl ester suppresses receptor activator of NF-kappaB ligand-induced osteoclastogenesis and prevents ovariectomy-induced bone loss through inhibition of mitogen-activated protein kinase/activator protein 1 and Ca2+-nuclear factor of activated T-cells cytoplasmic 1 signaling pathways J. Bone Miner. Res., 27 (6) (2012), pp. 1298-1308 CrossRefView Record in Scopus Wu et al., 2018 G. Wu, R. Xu, P. Zhang, T. Xiao, Y. Fu, Y. Zhang, Y. Du, J. Ye, J. Cheng, H. Jiang Estrogen regulates stemness and senescence of bone marrow stromal cells to prevent osteoporosis via ERbeta-SATB2 pathway J. Cell. Physiol., 233 (5) (2018), pp. 4194-4204 View Record in Scopus Xin et al., 2015 M. Xin, Y. Yang, D. Zhang, J. Wang, S. Chen, D. Zhou Attenuation of hind-limb suspension-induced bone loss by curcumin is associated with reduced oxidative stress and increased vitamin D receptor expression Osteoporos. Int., 26 (11) (2015), pp. 2665-2676 CrossRefView Record in Scopus Xu et al., 2010 D. Xu, W. Yang, C. Zhou, Y. Liu, B. Xu Preventive effects of berberine on glucocorticoid-induced osteoporosis in rats Planta Med., 76 (16) (2010), pp. 1809-1813 CrossRefView Record in Scopus Xu et al., 2016 D. Xu, Y. Lyu, X. Chen, X. Zhu, J. Feng, Y. Xu Fructus Ligustri Lucidi ethanol extract inhibits osteoclastogenesis in RAW264.7 cells via the RANKL signaling pathway Mol. Med. Rep., 14 (5) (2016), pp. 4767-4774 CrossRefView Record in Scopus Yamaguchi and Weitzmann, 2011 M. Yamaguchi, M.N. Weitzmann Quercetin, a potent suppressor of NF-kappaB and Smad activation in osteoblasts Int. J. Mol. Med., 28 (4) (2011), pp. 521-525 View Record in Scopus Yamaguchi et al., 2011 M. Yamaguchi, J.L. Arbiser, M.N. Weitzmann Honokiol stimulates osteoblastogenesis by suppressing NF-kappaB activation Int. J. Mol. Med., 28 (6) (2011), pp. 1049-1053 View Record in Scopus Yamaguchi et al., 2015 M. Yamaguchi, S. Zhu, M.N. Weitzmann, J.P. Snyder, M. Shoji Curcumin analog UBS109 prevents bone marrow osteoblastogenesis and osteoclastogenesis disordered by coculture with breast cancer MDA-MB-231 bone metastatic cells in vitro Mol. Cell. Biochem., 401 (1-2) (2015), pp. 1-10 CrossRefView Record in Scopus Yang et al., 2011 F. Yang, D.Z. Tang, X.J. Cui, J.D. Holz, Q. Bian, Q. Shi, Y.J. Wang Classic yin and yang tonic formula for osteopenia: study protocol for a randomized controlled trial Trials, 12 (2011), p. 187 CrossRefView Record in Scopus Yang et al., 2014 F. Yang, P.W. Yuan, Y.Q. Hao, Z.M. Lu Emodin enhances osteogenesis and inhibits adipogenesis BMC Complement. Altern. Med., 14 (2014), p. 74 ArticleDownload PDFCrossRefView Record in Scopus Yang et al., 2015 J. Yang, P. Andre, L. Ye, Y.Z. Yang The Hedgehog signalling pathway in bone formation Int J Oral Sci, 7 (2) (2015), pp. 73-79 CrossRefView Record in Scopus Yavropoulou and Yovos, 2007 M.P. Yavropoulou, J.G. Yovos The role of the Wnt signaling pathway in osteoblast commitment and differentiation Hormones (Athens), 6 (4) (2007), pp. 279-294 CrossRefView Record in Scopus Ying et al., 2015 X. Ying, X. Chen, H. Liu, P. Nie, X. Shui, Y. Shen, K. Yu, S. Cheng Silibinin alleviates high glucose-suppressed osteogenic differentiation of human bone marrow stromal cells via antioxidant effect and PI3K/Akt signaling Eur. J. Pharmacol., 765 (2015), pp. 394-401 ArticleDownload PDFView Record in Scopus Yu et al., 2015 T.Y. Yu, W.J. Pang, G.S. Yang 3,3'-Diindolylmethane increases bone mass by suppressing osteoclastic bone resorption in mice J. Pharmacol. Sci., 127 (1) (2015), pp. 75-82 ArticleDownload PDFView Record in Scopus Zainabadi et al., 2017 K. Zainabadi, C.J. Liu, L. Guarente SIRT1 is a positive regulator of the master osteoblast transcription factor, RUNX2 PLoS One, 12 (5) (2017), Article e0178520 CrossRef Zawawi et al., 2015 M.S. Zawawi, E. Perilli, R.L. Stansborough, V. Marino, M.D. Cantley, J. Xu, A.A. Dharmapatni, D.R. Haynes, R.J. Gibson, T.N. Crotti Caffeic acid phenethyl ester abrogates bone resorption in a murine calvarial model of polyethylene particle-induced osteolysis Calcif. Tissue Int., 96 (6) (2015), pp. 565-574 CrossRefView Record in Scopus Zhai et al., 2014 Z.J. Zhai, H.W. Li, G.W. Liu, X.H. Qu, B. Tian, W. Yan, Z. Lin, T.T. Tang, A. Qin, K.R. Dai Andrographolide suppresses RANKL-induced osteoclastogenesis in vitro and prevents inflammatory bone loss in vivo Br. J. Pharmacol., 171 (3) (2014), pp. 663-675 CrossRefView Record in Scopus Zhang et al., 2013 R. Zhang, B.O. Oyajobi, S.E. Harris, D. Chen, C. Tsao, H.W. Deng, M. Zhao Wnt/beta-catenin signaling activates bone morphogenetic protein 2 expression in osteoblasts Bone, 52 (1) (2013), pp. 145-156 ArticleDownload PDFView Record in Scopus Zhang et al., 2014 X. Zhang, J. Guo, Y. Zhou, G. Wu The roles of bone morphogenetic proteins and their signaling in the osteogenesis of adipose-derived stem cells Tissue Eng Part B Rev, 20 (1) (2014), pp. 84-92 CrossRefView Record in Scopus Zhang et al., 2015 X. Zhang, C. Zhou, X. Zha, Z. Xu, L. Li, Y. Liu, L. Xu, L. Cui, D. Xu, B. Zhu Apigenin promotes osteogenic differentiation of human mesenchymal stem cells through JNK and p38 MAPK pathways Mol. Cell. Biochem., 407 (1-2) (2015), pp. 41-50 CrossRefView Record in Scopus Zhang et al., 2016 L.Y. Zhang, H.G. Xue, J.Y. Chen, W. Chai, M. Ni Genistein induces adipogenic differentiation in human bone marrow mesenchymal stem cells and suppresses their osteogenic potential by upregulating PPARgamma Exp Ther Med, 11 (5) (2016), pp. 1853-1858 CrossRefView Record in Scopus Zhao et al., 2006 C. Zhao, N. Irie, Y. Takada, K. Shimoda, T. Miyamoto, T. Nishiwaki, T. Suda, K. Matsuo Bidirectional ephrinB2-EphB4 signaling controls bone homeostasis Cell Metab., 4 (2) (2006), pp. 111-121 ArticleDownload PDFView Record in Scopus Zhao et al., 2011 Y. Zhao, Y. Huai, J. Jin, M. Geng, J.X. Li Quinoxaline derivative of oleanolic acid inhibits osteoclastic bone resorption and prevents ovariectomy-induced bone loss Menopause, 18 (6) (2011), pp. 690-697 CrossRefView Record in Scopus Zhao et al., 2014 H. Zhao, X. Li, N. Li, T. Liu, J. Liu, Z. Li, H. Xiao, J. Li Long-term resveratrol treatment prevents ovariectomy-induced osteopenia in rats without hyperplastic effects on the uterus Br. J. Nutr., 111 (5) (2014), pp. 836-846 CrossRefView Record in Scopus Zhao et al., 2015 L. Zhao, Y. Wang, Z. Wang, Z. Xu, Q. Zhang, M. Yin Effects of dietary resveratrol on excess-iron-induced bone loss via antioxidative character J. Nutr. Biochem., 26 (11) (2015), pp. 1174-1182 ArticleDownload PDFView Record in Scopus Zheng et al., 2017 W. Zheng, H. Zhang, Y. Jin, Q. Wang, L. Chen, Z. Feng, H. Chen, Y. Wu Butein inhibits IL-1beta-induced inflammatory response in human osteoarthritis chondrocytes and slows the progression of osteoarthritis in mice Int. Immunopharmacol., 42 (2017), pp. 1-10 ArticleDownload PDFView Record in Scopus Zhou and Lin, 2014 C. Zhou, Y. Lin Osteogenic differentiation of adipose-derived stem cells promoted by quercetin Cell Prolif., 47 (2) (2014), pp. 124-132 CrossRefView Record in Scopus Zhou et al., 2015 Y. Zhou, Y. Wu, X. Jiang, X. Zhang, L. Xia, K. Lin, Y. Xu The Effect of Quercetin on the Osteogenesic Differentiation and Angiogenic Factor Expression of Bone Marrow-Derived Mesenchymal Stem Cells PLoS One, 10 (6) (2015), Article e0129605 CrossRef Zou et al., 2016 Y.C. Zou, X.W. Yang, S.G. Yuan, P. Zhang, Y.K. Li Celastrol inhibits prostaglandin E2-induced proliferation and osteogenic differentiation of fibroblasts isolated from ankylosing spondylitis hip tissues in vitro Drug Des Devel Ther, 10 (2016), pp. 933-948 View Record in Scopus Zwerina et al., 2007 J. Zwerina, K. Redlich, K. Polzer, L. Joosten, G. Kronke, J. Distler, A. Hess, N. Pundt, T. Pap, O. Hoffmann, J. Gasser, C. Scheinecker, J.S. Smolen, W. van den Berg, G. Schett TNF-induced structural joint damage is mediated by IL-1 Proc. Natl. Acad. Sci. U. S. A., 104 (28) (2007), pp. 11742-11747 CrossRefView Record in Scopus Published by Elsevier Inc.