The RANK/RANKL/OPG system in tumorigenesis and metastasis of cancer stem cell: potential targets for anticancer therapy

Figures & data

Figure 1 The role of RANK/RANKL signaling system in various physiological and pathophysiological processes.

Abbreviations: RANK, receptor activator of nuclear factor kβ; RANKL, RANK ligand.

Table 1 The role of RANKL/RANK/OPG system in primary malignant tumors of the bone

Primary bone tumors	RANKL/RANK/OPG system and its role in tumorigenesis	References
Osteosarcoma	– ↑ RANKL/OPG ratio was observed in the serum of patients with osteosarcoma	Grimaud et al^Citation17
	– In experimental animals, OPG treatment achieved not only the prevention of osteosarcoma-induced osteolysis but also the inhibition of associated tumor development that improved the survival rate in treatment groups	Lamoureux et al^Citation18
	– RANKL blockade has been shown to prevent and treat aggressive osteosarcomas	Chen et al^Citation19
Multiple myeloma	Deregulation of the triad system (expression of more RANKL and/or more lysosomal degradation of OPG) enhances osteoclastogenesis	Pearse et al^Citation20
GCTB	↑ RANKL/OPG ratio was also observed in GCTB
	The stromal cells within GCTB had increased RANKL/OPG ratio compared to that of non-osteolytic bone tumors	Lewin and Thomas^Citation21

Note: ↑, increased, high.

Abbreviations: GCTB, giant cell tumor of the bone; OPG, osteoprotegerin; RANK, receptor activator of nuclear factor kβ; RANKL, RANK ligand.

Table 2 The role of RANK/RANKL/OPG system in the development and metastasis of solid cancers

Solid cancers	Methods	Observed molecular mechanisms and effects	References
Breast cancer	RANK and RANKL gene knockout in mice models (in vivo study)	– Immature lobuloalveolar development (disorganized mammary gland structure) and disabled milk production	Fata et al^Citation5
		– RANKL-driven hormone (progesterone) dependent proliferation, survival, and expansion of mammary stem cell could each contribute to mammary cancer initiation, progression, and recurrence	Dougall^Citation23
	Site directed mutagenesis (in mice model) and RANKL blockage	– Gain of function mutation of RANK signaling resulted in ↑ formation of pre-neoplasias and tumors, whereas inhibition of RANKL ↓ tumorigenesis	Gonzalez-Suarez et al^Citation24
	RANK gene knockout or loss of function mutation in mice model and RANKL treatment	– ↓ and retarded progestin (MPA)-driven breast cancer – RANKL addition ↓ cell death in response to antitumor antibiotics and irradiation	Schramek et al^Citation32
	In vitro studies (MDA-MB-436/231 breast cancer cells)	– ↑ Expression of RANK, RANKL, and OPG. OPG acts as a decoy receptor for TRAIL and thereby inhibits apoptosis of a range of tumor cells (survival signal for breast cancer cells)	Emery et al^Citation33 Holen et al^Citation34
	Cancer patients (correlation of Kaplan–Meier survival analysis with serum samples of RANK and OPG)	– ↓ Expression of serum OPG → better overall survival of patients (quantity of life in years) – ↑ RANK and ↓ OPG expression → ↑ metastasis of breast cancer to bone	Santini et al;^Citation22 Owen et al^Citation35
		– However, contradictory results on OPG were observed  • In bone, OPG reduces bone loss (osteolysis) due to breast cancer metastasis; however, in breast cancer, OPG ↓ apoptosis of cancer cell (↑ survival and invasiveness)	Weichhaus et al^Citation36
	Experimental investigations (breast cancer patients) plus in vitro study (RANKL producing CD4^+CD25^+ T-cells)	– High expression of CD4^+CD25^+FoxP3^+ Treg cells ↑ aggressiveness of breast cancer phenotype and ↑ RANKL production (major source)	Tan et al^Citation37
	4T1 and NMuMG cells (ATCC) and MCF 7 cells (lentiviral infection to induce tumorigenesis in normal cells)	– In ER^− and PR^− breast cancer cells → more expression of RANK mRNA levels and generally have poorer prognosis and high degree of invasiveness than controls. Moreover, RANK overexpression has also been demonstrated to induce epithelial to mesenchymal transition and stemness	Palafox et al;^Citation38 Tsubaki et al^Citation39
	In vitro study on human MDA-MB-231 breast cancer cell lines (MDA-231-RANK cells)	– MDA-MB-231 cells with high RANK expression resulted in greater metastatic growth rate. However, MDA-MB-231 cells with low RANK level primarily remain in situ – Administration of RANKL for these cells  • ⇑ expression of multiple genes associated with cell invasive behavior (including several matrix metalloproteinases and other genes that can be considered as a bone metastasis gene signature	Blake et al^Citation40
	Primary breast cancer samples from the neoadjuvant GeparTrio study (in vitro) plus in vivo experimental study (mice model)	– Pharmacologic inhibition of RANKL attenuates tumor development and metastasis in mice – High RANK expression  • Higher sensitivity to chemotherapy but a higher risk of relapse and death	Pfitzner et al^Citation41
	A nested case–control study	– Higher concentrations of OPG were associated with increased risk of ER^− breast cancer but less likely in ER^+ type	Fortner et al^Citation42
	Human breast epithelial cells with Brca1 haploinsufficiency cell	– Denosumab has been proposed to interfere with the cross talk between RANKL producing sensor cells and cancer initiating RANK^+ responder cells that reside within premalignant tissues of Brca1-mutation carriers	Cuyàs et al^Citation43
	Case control study	– Brca1-mutation carriers had lower mean values of free serum OPG, in particular, in Brca1-mutation carriers (P=0.018) compared with controls	Widschwendter et al^Citation44
	Human case reports	– RANK and RANKL coexpression is associated with poor RFS and OS in patients with TNBC	Reyes et al^Citation45
	Surgical biopsy sample of prostate cancer patients and in vitro studies (normal human prostate cells, PrEC and human prostate cancer cell lines-LNCaP, DU-145, and PC-3 cells)	– In prostate cancer cells, ↑ RANK, RANKL, and OPG expression was observed indicating more aggressive and advanced stage; however, normal cells have negligible expression of these proteins	Chen et al^Citation46
Prostate cancer	Comparative study on hormone-insensitive prostate cancer cell lines (PC-3 and DU-145) and hormone-sensitive cell line (LNCaP) under the same conditions	– OPG is considered as a survival factor for prostate cancer cells by blocking TRAIL	Holen et al^Citation47
	Metastatic cancer cell models	– RANKL → ↑ IKKα (active) and ↓ Maspin (metastasis suppressor protein) leading to disease progression and tumor invasiveness	Luo et al^Citation48
	ARCaP(E)/ARCaP(M) prostate cancer model and LNCaP clones overexpressing Snail in a stable manner	– RANKL expression upregulates mesenchymal-associated genes (morphogenic conversion from epithelial to mesenchymal type) → more tumor invasiveness (loss of cell to cell adhesion)	Odero-Marah et al^Citation49
	In murine model of prostate cancer (PC-3) cells, observation of the effect of RANKL inhibitor and/or antimitotic agent (docetaxel)	– Inhibition of RANKL significantly reduced pathologic osteolysis and ⇑ antitumor effect of docetaxel leading to ↓ skeletal tumor burden and prolonged survival	Miller et al^Citation50
	Case control study (enzyme-linked immunosorbent assay)	– Higher OPG and PSA concentrations have been observed in metastatic bone patients’ sera. It seems that elevated levels of serum OPG in patients with prostate cancer reflect the bone metastatic extent and may potentially be used in metastatic patients’ follow-ups	Siampanopoulou et al^Citation51
	Experimental study on murine model (non-castration, castration, and castration + OPG groups)	– The mechanisms of RANK/RANKL signaling are involved in the ADT-induced acceleration of bone metastasis in castration-insensitive prostate cancer	Takayama et al^Citation52
Lung cancer	Model of lung cancer (human lung cancer [A549] cells)	– RANKL → upregulation ICAM-1 → ↑ tumor migration	Chen et al^Citation53
	Experimental investigation in human patients and case reports	– Denosumab ameliorated ALK-induced lung cancer  • Inhibition of RANK → ↓ PI3K activation → downregulation of Akt/Pkβ (ALK fusion protein downstream signaling)	Curioni-Fontecedro et al^Citation54
	(NSCLC) bone metastasis models Radiography, longitudinal bioluminescent imaging, and histological analyses	– Recombinant version of OPG (OPG-Fc) ↓ osteolytic lesions and significantly reduce skeletal tumor burden in NSCLC cells	Miller et al^Citation55
RCC	Histopathologic study of RCC patients with RTQPCR	– In clear cell RCCs, ⇑ RANK mRNA expression ↑ RANK/OPG ratio and low disease-free survival were observed	Mikami et al^Citation56
HCC	Case report in virus-induced HCC patients	– In hepatitis C virus and hepatitis B virus-induced HCC  • RANKL expression → invasiveness and metastasis to bone	Sasaki et al^Citation57
Melanoma	In vivo study on malignant tumor of melanocytes	– RANKL blockage → ↓ bone metastasis and morbidity	Jones et al^Citation58
	In vivo study targeting the thymus gland (AIRE)	– RANKL blockage → depletes AIRE that expresses MTEC and TSA expression in the thymus gland leading to a window of defective negative selection, rescue melanoma-specific T-cells from thymic deletion and ↑ host survival secondary to tumor challenge	Khan et al^Citation59

Notes: ↑, increased, unregulated; ↓, decreased, downregulated, attenuated.

Abbreviations: ADT, androgen deprivation therapy; AIRE, autoimmune regulator gene; ALK, anaplastic lymphoma kinase; ATCC, American type cell culture; ER, estrogen receptor; HCC, hepatocellular carcinoma; ICAM-1, intercellular adhesion molecule-1; MTEC, medullary thymic epithelial cells; NSCLC, non-small-cell lung cancer; OPG, osteoprotegerin; OS, overall survival; PkB, protein kinase B; PR, progestin receptor; PSA, prostate-specific antigens; RANK, receptor activator of nuclear factor kβ; RANKL, RANK ligand; RCC, renal cell carcinoma; RFS, relapse-free survival; RTQPCR, real-time quantitative polymerase chain reaction; TNBC, triple-negative breast cancer; TRAIL, tumor necrosis factor-related apoptosis inducing ligand; Treg, Regulatory T-cells; TSA, tumor-specific antigens.

Figure 2 The role of Cbl-b in RANKL-induced breast cancer cell migration and metastasis.

Notes: (A) Cbl-b protein inhibited RANKL-induced breast cancer cell migration and metastasis; (B) Cbl-b downregulated RANK protein expression by negatively regulating the Src-Akt/ERK pathway.
Abbreviations: ERK, extracellular signal regulated kinase; RANK, receptor activator of nuclear factor kβ; RANKL, RANK ligand.

Table 3 Potential therapeutic agents targeting this signaling system

Therapeutic classes	Examples	Molecular mechanisms and effects	References
Monoclonal antibodies (humanized)	Denosumab	– It binds with RANKL (antigen–antibody interaction) and interrupts RANK–RANKL interaction. It mimics the antagonistic effect of OPG but it does not affect TRAIL and thereby prevents cancer cell survival and migration. It was approved by FDA for treatment	Kostenuik et al;^Citation67 Peddi et al^Citation68
		– Prolonged treatment with denosumab has sustained activity in GCTB, with a mild toxicity profile	Palmerini et al^Citation69
		– Systemic therapy inhibits bone resorption by osteoclast-like giant cells	van der Heijden et al^Citation70
		– Notably, proliferation was markedly reduced in breast biopsies from Brca1-mutation carriers that were treated with denosumab	Nolan et al^Citation71
Osteoprotegerin-like peptidomimetics	OP3–4	– Selective inhibitors of RANKL without affecting TRAIL	Heath et al^Citation72
RANK receptor inhibitors	–	– Targets the cytoplasmic motifs of RANK receptor	Kim et al^Citation73
Peptide RANK antagonists	Novel nonapeptide series	– Targets hinge region of RANK receptor	Téletchéa et al^Citation74
Proteolytic enzymes	Enteropeptidase	– Cleavage of RANK on NEEDK amino acid sequences	Zhao et al^Citation75
RANKL targeting peptides	–	– Based on the molecular modeling (3D structure) of OPG	Naidu et al^Citation76
RNA interference technology	Small hairpin RNAs	– Targets interruption of RANK expression	Ma et al^Citation77
Organic acid derivatives	Strontium ranelate	– ↑ OPG mRNA expression and secretion	Brennan et al^Citation78
Anti-inflammatory drugs	Chloroquine	– ↓ RANKL expression – ↑ TRAF3 production	Xiu et al^Citation79
Herbal medicines	Jolkinolide B	– Root of Euphorbia fischeriana (source) ↓ RANKL-induced activation of NF-κB by suppressing RANKL-mediated IκBα degradation	Ma et al^Citation80
	WEAT	– Inhibited RANKL-induced activation of JNK, NF-κB, and CREB leading to suppression of the induction of c-Fos and NFATc1 (key transcription factors for osteoclast differentiation)	Ha et al^Citation81
Other agents	Afatinib	– It significantly suppresses RANKL-induced osteoclast formation in BMMs. Consistently, it inhibits the expression of osteoclast marker genes, whereas it upregulates the expression of negative modulator genes. The bone resorbing activity of osteoclasts is also abrogated by afatinib. In addition, it inhibits RANKL-mediated Akt/protein kinase B and c-Jun N-terminal kinase phosphorylation	Ihn et al^Citation82

Notes: ↑, increased, unregulated; ↓, decreased, downregulated, attenuated.

Abbreviations: BMM, bone marrow macrophages; CREB, cAMP response element-binding protein; FDA, US Food and Drug Administration; GCTB, giant cell tumor of the bone; JNK, Jun N-terminal kinase; NF-κB, nuclear factor kappa B; OPG, osteoprotegerin; RANK, receptor activator of nuclear factor kβ; RANKL, RANK ligand; WEAT, water extract of Acer tegmentosum; 3D, three-dimensional; TRAIL, tumor necrosis factor-related apoptosis inducing ligand; NEEDK, aspargine, glutamic acid, glutamic acid, aspartic acid and lysine; TRAF, tumor necrosis factor receptor associated factor.

GrimaudESoubigouLCouillaudSReceptor activator of nuclear factor κB ligand (RANKL)/osteoprotegerin (OPG) ratio is increased in severe osteolysisAm J Pathol200316352021203114578201

 PubMedGoogle Scholar

LamoureuxFRichardPWittrantYTherapeutic relevance of osteoprotegerin gene therapy in osteosarcoma: blockade of the vicious cycle between tumor cell proliferation and bone resorptionCancer Res200767157308731817671200

 PubMed Web of Science ®Google Scholar

ChenYDi GrappaMAMolyneuxSDRANKL blockade prevents and treats aggressive osteosarcomasSci Transl Med20157317317ra197

 PubMed Web of Science ®Google Scholar

PearseRNSordilloEMYaccobySMultiple myeloma disrupts the TRANCE/osteoprotegerin cytokine axis to trigger bone destruction and promote tumor progressionProc Natl Acad Sci U S A20019820115811158611562486

 PubMedGoogle Scholar

LewinJThomasDDenosumab: a new treatment option for giant cell tumor of boneDrugs Today (Barc)2013491169370024308016

 PubMedGoogle Scholar

FataJEKongYYLiJThe osteoclast differentiation factor osteoprotegerin-ligand is essential for mammary gland developmentCell20001031415011051546

 PubMed Web of Science ®Google Scholar

DougallWCMolecular pathways: osteoclast-dependent and osteoclast-independent roles of the RANKL/RANK/OPG pathway in tumorigenesis and metastasisClin Cancer Res201218232633522031096

 PubMed Web of Science ®Google Scholar

Gonzalez-SuarezEJacobAPJonesJRANK ligand mediates progestin-induced mammary epithelial proliferation and carcinogenesisNature2010468732010310720881963

 PubMed Web of Science ®Google Scholar

SchramekDLeibbrandtASiglVOsteoclast differentiation factor RANKL controls development of progestin-driven mammary cancerNature201046873209810220881962

 PubMed Web of Science ®Google Scholar

EmeryJGMcDonnellPBurkeMBOsteoprotegerin is a receptor for the cytotoxic ligand TRAILJ Biol Chem19982732314363143679603945

 PubMed Web of Science ®Google Scholar

HolenICrossSSNeville-WebbeHLOsteoprotegerin (OPG) expression by breast cancer cells in vitro and breast tumours in vivo – a role in tumour cell survival?Breast Cancer Res Treat200592320721516155791

 PubMed Web of Science ®Google Scholar

SantiniDPerroneGRoatoIExpression pattern of receptor activator of NFκB (RANK) in a series of primary solid tumors and related bone metastasesJ Cell Physiol2011226378078420857484

 PubMed Web of Science ®Google Scholar

OwenSYeLSandersAJMasonMDJiangWGExpression profile of receptor activator of nuclear-κB (RANK), RANK ligand (RANKL) and osteoprotegerin (OPG) in breast cancerAnticancer Res201333119920623267146

 PubMed Web of Science ®Google Scholar

WeichhausMChungSTConnellyLOsteoprotegerin in breast cancer: beyond bone remodelingMol Cancer201514111726054853

 PubMedGoogle Scholar

TanWZhangWStrasnerATumour-infiltrating regulatory T cells stimulate mammary cancer metastasis through RANKL-RANK signallingNature2011470733554855321326202

 PubMed Web of Science ®Google Scholar

PalafoxMFerrerIPellegriniPRANK induces epithelial–mesenchymal transition and stemness in human mammary epithelial cells and promotes tumorigenesis and metastasisCancer Res201272112879288822496457

 PubMed Web of Science ®Google Scholar

TsubakiMKomaiMFujimotoSIActivation of NF-κB by the RANKL/RANK system up-regulates snail and twist expressions and induces epithelial-to-mesenchymal transition in mammary tumor cell linesJ Exp Clin Cancer Res2013326224011086

 PubMed Web of Science ®Google Scholar

BlakeMLTometskoMMillerRJonesJCDougallWCRANK expression on breast cancer cells promotes skeletal metastasisClin Exp Metastasis201431223324524272640

 PubMed Web of Science ®Google Scholar

PfitznerBMBranstetterDLoiblSRANK expression as a prognostic and predictive marker in breast cancerBreast Cancer Res Treat2014145230731524737168

 PubMedGoogle Scholar

FortnerRTSarinkDSchockHOsteoprotegerin and breast cancer risk by hormone receptor subtype: a nested case-control study in the EPIC cohortBMC Med2017152628173834

 PubMedGoogle Scholar

CuyàsECorominas-FajaBMartínMMBRCA1 haplo insufficiency cell-autonomously activates RANKL expression and generates denosumab-responsive breast cancer-initiating cellsOncotarget2017821350193503228388533

 PubMedGoogle Scholar

WidschwendterMBurnellMFraserLOsteoprotegerin (OPG), the endogenous inhibitor of receptor activator of NF-κB ligand (RANKL), is dysregulated in BRCA mutation carriersBioMedicine201521013311339

 Google Scholar

ReyesMEFujiiTBranstetterDPoor prognosis of patients with triple-negative breast cancer can be stratified by RANK and RANKL dual expressionBreast Cancer Res Treat20171641576728417335

 PubMedGoogle Scholar

ChenGSircarKAprikianAPottiAGoltzmanDRabbaniSAExpression of RANKL/RANK/OPG in primary and metastatic human prostate cancer as markers of disease stage and functional regulationCancer2006107228929816752412

 PubMed Web of Science ®Google Scholar

HolenICroucherPIHamdyFCEatonCLOsteoprotegerin (OPG) is a survival factor for human prostate cancer cellsCancer Res20026261619162311912131

 PubMedGoogle Scholar

LuoJLTanWRiconoJMNuclear cytokine-activated IKKα controls prostate cancer metastasis by repressing MaspinNature2007446713669069417377533

 PubMedGoogle Scholar

Odero-MarahVAWangRChuGReceptor activator of NF-κB ligand (RANKL) expression is associated with epithelial to mesenchymal transition in human prostate cancer cellsCell Res200818885887018645583

 PubMed Web of Science ®Google Scholar

MillerRERoudierMJonesJArmstrongACanonJDougallWCRANK ligand inhibition plus docetaxel improves survival and reduces tumor burden in a murine model of prostate cancer bone metastasisMol Cancer Ther2008772160216918606716

 PubMed Web of Science ®Google Scholar

SiampanopoulouMEl Mantani OrdoulidisSMoustakasGThe role of serum osteoprotegerin in metastatic prostate cancer – a case control studyHippokratia201620213313828416910

 PubMedGoogle Scholar

TakayamaKInoueTNaritaSInhibition of the RANK/RANKL signaling with osteoprotegerin prevents castration-induced acceleration of bone metastasis in castration-insensitive prostate cancerCancer Lett201739710311028373003

 PubMed Web of Science ®Google Scholar

ChenLMKuoCHLaiTYRANKL increases migration of human lung cancer cells through intercellular adhesion molecule-1 up-regulationJ Cell Biochem2011112393394121328467

 PubMedGoogle Scholar

Curioni-FontecedroAHusmannLSoldiniDStahelRAPrimary non-small cell lung cancer response upon treatment with denosumabLung Cancer201382350650824075124

 PubMedGoogle Scholar

MillerREJonesJCTometskoMBlakeMLDougallWCRANKL inhibition blocks osteolytic lesions and reduces skeletal tumor burden in models of non-small-cell lung cancer bone metastasesJ Thorac Oncol20149334535424496001

 PubMedGoogle Scholar

MikamiSKatsubeKIOyaMIncreased RANKL expression is related to tumour migration and metastasis of renal cell carcinomasJ Pathol2009218453053919455604

 PubMed Web of Science ®Google Scholar

SasakiAIshikawaKHaraguchiNReceptor activator of nuclear factor-κB ligand (RANKL) expression in hepatocellular carcinoma with bone metastasisAnn Surg Oncol20071431191119917195907

 PubMed Web of Science ®Google Scholar

JonesDHNakashimaTSanchezOHRegulation of cancer cell migration and bone metastasis by RANKLNature2006440708469269616572175

 PubMed Web of Science ®Google Scholar

KhanISMouchessMLZhuMLEnhancement of an anti-tumor immune response by transient blockade of central T cell toleranceJ Exp Med2014211576176824752296

 PubMedGoogle Scholar

KostenuikPJNguyenHQMcCabeJDenosumab, a fully human monoclonal antibody to RANKL, inhibits bone resorption and increases BMD in knock-in mice that express chimeric (murine/human) RANKLJ Bone Miner Res200924218219519016581

 PubMed Web of Science ®Google Scholar

PeddiPLopez-OlivoMAPrattGFSuarez-AlmazorMEDenosumab in patients with cancer and skeletal metastases: a systematic review and meta-analysisCancer Treat Rev20133919710422898302

 PubMed Web of Science ®Google Scholar

PalmeriniEChawlaNSFerrariSDenosumab in advanced/unresectable giant-cell tumour of bone (GCTB): for how long?Eur J Cancer20177611812428324746

 PubMed Web of Science ®Google Scholar

van der HeijdenLDijkstraPDSBlayJYGelderblomHGiant cell tumour of bone in the denosumab eraEur J Cancer201777758328365529

 PubMed Web of Science ®Google Scholar

NolanEVaillantFBranstetterDRANK ligand as a potential target for breast cancer prevention in BRCA1-mutation carriersNat Med201622893393927322743

 PubMed Web of Science ®Google Scholar

HeathDJVanderkerkenKChengXAn osteoprotegerin-like peptidomimetic inhibits osteoclastic bone resorption and osteolytic bone disease in myelomaCancer Res200767120220817210700

 PubMedGoogle Scholar

KimHChoiHKShinJHSelective inhibition of RANK blocks osteoclast maturation and function and prevents bone loss in miceJ Clin Invest2009119481382519258703

 PubMedGoogle Scholar

TéletchéaSStresingVHervouetSNovel RANK antagonists for the treatment of bone-resorptive disease: theoretical predictions and experimental validationJ Bone Miner Res20142961466147724390798

 PubMedGoogle Scholar

ZhaoYJinMMaJInhibition effect of enteropeptidase on RANKL–RANK signalling by cleavage of RANKFEBS Lett2013587182958296423954298

 PubMed Web of Science ®Google Scholar

NaiduVGBabuKRThwinMMSatishRLKumarPVGopalakrishnakonePRANKL targeted peptides inhibit osteoclastogenesis and attenuate adjuvant induced arthritis by inhibiting NF-κB activation and down regulating inflammatory cytokinesChem Biol Interact2013203246747923333834

 PubMed Web of Science ®Google Scholar

MaRXuJDongBKautherMDJägerMWedemeyerCInhibition of osteoclastogenesis by RNA interference targeting RANKBMC Musculoskelet Disord20121315422913338

 PubMedGoogle Scholar

BrennanTCRybchynMSGreenWAtwaSConigraveADMasonRSOsteoblasts play key roles in the mechanisms of action of strontium ranelateBr J Pharmacol200915771291130019563530

 PubMed Web of Science ®Google Scholar

XiuYXuHZhaoCChloroquine reduces osteoclastogenesis in murine osteoporosis by preventing TRAF3 degradationJ Clin Invest2014124129731024316970

 PubMed Web of Science ®Google Scholar

MaXLiuYZhangYYuXWangWZhaoDJolkinolide B inhibits RANKL-induced osteoclastogenesis by suppressing the activation NF-κB and MAPK signaling pathwaysBiochem Biophys Res Commun2014445228228824491533

 PubMed Web of Science ®Google Scholar

HaHShimKSKimTWater extract of Acer tegmentosum reduces bone destruction by inhibiting osteoclast differentiation and functionMolecules20141943940395424694651

 PubMedGoogle Scholar

IhnHJKimJABaeYCShinHIBaekMCParkEKAfatinib ameliorates osteoclast differentiation and function through downregulation of RANK signaling pathwaysBMB Rep201750315015528256196

 PubMedGoogle Scholar