• Mekonnen Sisay Department of pharmacology and Toxicology, School of Pharmacy, College of Health and Medical Sciences, Haramaya University, Harar, Eastern Ethiopia.
  • Jemal Abdela Department of pharmacology and Toxicology, School of Pharmacy, College of Health and Medical Sciences, Haramaya University, Harar, Eastern Ethiopia.
  • Yallew Molla Department of Pharmacology, College of Health Sciences, Debre Markos University, Gojam, Ethiopia


Metabolic bone diseases are disorders of bone strength, usually caused by abnormalities of minerals (such as calcium or phosphorus), vitamin D, bone mass and/or structure. The most common metabolic bone disease is osteoporosis. It is a progressive bone disease that is characterized by a decrease in bone mass and density which can lead to an increased risk of fracture. This review was aimed at summarizing a plenty of literatures related to the impact of RANK/RANKL/OPG system on bone metabolic diseases and therapeutic agents targeting it. Data were collected from several legitimate data bases and services such as Pubmed, Pub med central, Medline, Hinari, Scopus, and other data base sources like Crossref, and Google scholar with the help of key words (RANK/RANKL/OPG system, metabolic bone diseases etc.). Important data on the topic of interest were filtered properly. The role of RANK/RANKL/OPG system is well characterized within bone, where RANKL-RANK signaling mediates osteoclastogenesis, osteoclast activation and bone resorption via paracrine signaling between osteoblast and osteoclast cells. OPG produced by osteoblast and stromal cells in bone acts as a natural RANKL antagonist (decoy receptor) that intereferes with RANKL-RANK binding and hence prevents osteoclast differentiation and activation. This system and its interaction with various cytokines and calciotropic hormones in the regulation of osteoclastogenesis has led to a new era for further understanding of the pathophysiology of several disorders of bone metabolism including osteoporosis, primary bone tumors and rheumatoid arthritis. The system has also resulted in the recognition of several rare genetic disorders of bone mineral metabolism such as paget's disease, familial expansile osteolysis and osteopetrosis. Since this cytokine system plays a major role in the pathogenesis of many disorders, several therapeutic agents targeting this system are being developed. Among them, denosumab, a monoclonal antibody against RANKL, is clinically approved for the treatment of osteoporosis and cancer-related bone diseases.

Key words: RANK/RANKL/OPG system, metabolic bone diseases, potential therapeutic approaches

Keywords: therapeutics


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Author Biographies

Mekonnen Sisay, Department of pharmacology and Toxicology, School of Pharmacy, College of Health and Medical Sciences, Haramaya University, Harar, Eastern Ethiopia.

Department of pharmacology and Toxicology, School of Pharmacy, College of Health and Medical Sciences, Haramaya University, Harar, Eastern Ethiopia.

Jemal Abdela, Department of pharmacology and Toxicology, School of Pharmacy, College of Health and Medical Sciences, Haramaya University, Harar, Eastern Ethiopia.

Department of pharmacology and Toxicology, School of Pharmacy, College of Health and Medical Sciences, Haramaya University, Harar, Eastern Ethiopia.

Yallew Molla, Department of Pharmacology, College of Health Sciences, Debre Markos University, Gojam, Ethiopia
Department of Pharmacology, College of Health Sciences, Debre Markos University, Gojam, Ethiopia


1. Offermanns S, Rosenthal W. Encyclopedia of Molecular Pharmacology. 2008. 2nd ed. Spriger. PP 277-279.
2. Neve A, Corrado A, Cantatore FP., Osteoblast physiology in normal and pathological conditions, Cell and Tissue Research 2011; 343:289–302.
3. Roodman GD., Cell biology of the osteoclast, Experimental Hematology 1999; 27:1229–41.
4. Teitelbaum SL, Ross FP. Genetic regulation of osteoclast development and function, Natural Revolutionary Genetics 2003;4: 638-49
5. Charles RC, Robert ES. Modern Pharmacology with clinical applications. In : Schwartz FL. Parathyroid Hormone, Calcitonin, Vitamin D, and other compounds related to mineral metabolism. Chapter 66. 2010; 5th ed. pp759-60
6. Laurence LB. Goodman & Gilman's the pharmacological basis of therapeutics. In: Agents Affecting Mineral Ion Homeostasis and Bone Turnover. The McGraw-Hill Companies. 2010; 12th ed. California.
7. Katzung BG. Basic and Clinical Pharmacology. In: Bikle DD. Agents that affect bone mineral homeostasis, chapter 12, McGraw-Hill Companies. 2012; 12th ed.PP 782
8. WHO. Assessment of fracture risks and its application to screening for postmenopausal osteoporosis, Report of a WHO Study Group, World Health Organization technical report series 1994;843: 1–129
9. Ginaldi L, Benedetto M C, Martinis M. Osteoporosis, inflammation and ageing, immunity & Ageing 2005; 2 :14
10. Teng GG, Curtis JR, Saag KG. Mortality and osteoporotic fractures: Is the link causal, and is it modifiable? Clin Exp Rheumatol, 2008, 26:S125–S137.
11. Joyce MJ. Primary malignant bone tumors. 2012;
Available at: disorders/tumors-of-bones-and-joints
12. Roodman GD. Windle JJ. Paget disease of bone. J Clin Invest. 2005; 115:200–08.
13. Felix R, Cecchini MG, Hofstetter W., Recent developments on the understanding of the pathophysiology of osteopetrosis, European Journal of Endocrinology 2003; 134:143–56.
14. Hofbauer LC, Heufelder, Armin E. Role of receptor activator of nuclear factor-κB ligand and osteoprotegerin in bone cell biology, Journal of Molecular Medicine 2001; 79:243–53
15. Galibert L,Tometsko ME, Anderson DM. The involvement of multiple tumor necrosis factor receptor (TNFR)-associated factors in the signaling mechanisms of receptor activator of NF-kappaB, a member of the TNFR superfamily, Jouranal of Biological Chemistry1998; 273: 34120-7.
16. Wong BR, Rho J, Arron J. TRANCE is a novel ligand of the tumor necrosis factor receptor family that activates c-Jun N-terminal Kinase in T cells, Journal of Biological Chemistry 1997; 272:25190–4.
17. Boyce BF, Xing L. Biology of RANK, RANKL, and osteoprotegerin. Arthritis Res Ther. 2007;9(1):1.
18. Fata JE, Kong YY, Li J, Sasaki T, Irie-Sasaki J, Moorehead RA, et al. The osteoclast differentiation factor osteoprotegerin-ligand is essential for mammary gland development. Cell;103(1):41-50.
19. Cheng ML, Fong L. Effects of RANKL-targeted therapy in immunity and cancer. Front Oncol. 2014;3:329. doi:10.3389/fonc.2013.00329.
20. Han ad a R, Le ibbrand t A, Hanada T , Kitaoka S, Fu ruyas hiki T , Fu jihara H, et al. Cen tral control of fever and female body temperature by RANKL/RANK. Nature. 2009;462(7272):505- 9
21. Hanada R. The new function of RANKL/RANK system in the central nervous systems. Neurosci Res. 2011 Sep;71:e22.
22. Dougall WC. Molecular Pathways: Osteoclast-Dependent and Osteoclast-Independent Roles of the RANKL/RANK/OPG Pathway in Tumorigenesis and Metastasis, Clinical Cancer Research 2011; 18:326–35
23. Hofbauer LC, Kühne CA, Viereck V. The OPG/RANKL/RANK system in metabolic bone diseases, Journal of Musculoskeletal and Neuron Interaction 2004; 4:268-75
24. Teitelbaum SL., Bone resorption by osteoclast, Science 2000; 289:1504-08
25. Riggs BL. the mechanisms of estrogen regulation of bone resorption, journal of clinical investigation 2000; 106 :10
26. Hofbauer LC, Khosla S, Dunstan CR, et al. Estrogen stimulates gene expression and protein production of osteoprotegerin in human osteoblastic cells, Endocrinology 1999; 140:4367-70.
27. Saika M, Inoue D, Kido S, et a1. 17 β-Estradiol stimulates expression of osteoprotegerin by a mouse stromal cell line, ST-2, via estrogen receptor, Endocrinology 2001; 142:2205-12.
28. Chen XW, Garner SC, Anderson JJ. Isoflavones regulate interleukin-6 and osteoprotegerin synthesis during osteoblast cell differentiation via an estrogen-receptor-dependent pathway, Biochemical and Biophysical Research Communication 2002; 295:417-22.
29. Shevde NK, Bendixen AC, Dienger KM. et al. Estrogens suppress RANK ligand-induced osteoclast differentiation via a stromal cell independent mechanism involving c-Jun repression, Proceeding national academy of sciences 2000; 97:7829 –34
30. Hofbauer LC, Gori F, Riggs BL. Stimulation of osteoprotegerin ligand and inhibition of osteoprotegerin production by glucocorticoids in human osteoblastic lineage cells: potential paracrine mechanisms of glucocorticoid induced osteoporosis, Endocrinology 1999;140:4382-9.
31. Kitazawa R, Kitazawa S, Maeda S. Promoter structure of mouse RANKL/TRANCE/OPGL/ODF gene, Biochemical and Biophysical research communications 1999; 1445 :134–41
32. Vidal NOA, Brändström H, Jonsson KB, et al. Osteoprotegerin mRNA is expressed in primary human osteoblast-like cells: down-regulation by glucocorticoids, Journal of Endocrinology 1998; 159:191–5.
33. Sasaki N, Kusano E, Ando Y, et al. Changes in osteoprotegerin and markers of bone metabolism during glucocorticoid treatment in patients with chronic glomerulonephritis, Bone 2002; 30:853–58
34. Von-Tirpitz C, Epp S, Klaus J, et al. Effect of systemic glucocorticoid therapy on bone metabolism and the osteoprotegerin system in patients with active Crohn’s disease, European Journal of Gastroenterology and Hepatology 2003; 15:1165–70
35. Ueland T, Bollerslev J, Godang K, et al. Increased serum osteoprotegerin in disor-ders characterized by persistent immune activation or glucocorticoid excess – possible role in bone homeostasis, European Journal of Endocrinology 2001; 145:685-90.
36. Hofbauer LC, Shui C, Riggs BL, et al. Effects of immunosuppressants on receptor activator of NF-kB ligand and osteoprotegerin production by human osteoblastic and coronary artery smooth muscle cells, Biochemical and Biophysical Research Communication 2001; 280:334-9
37. Rubin J, Murphy T, Nanes MS, et al. Mechanical strain inhibits expression of osteoclast differentiation factor by murine stromal cells, American Journal of Physiology Cell Physiology 2000; 278:1126-32.
38. Rubin J, Murphy TC, Fan X, et al. Activation of extracellular signal-regulated kinase is involved in mechanical strain inhibition of RANKL expression in bone stromal cells, Jouranal of Bone Mineral Research 2002 17:1452-60
39. Bateman TA, Dunstan CR, Ferguson VL, et al. Osteoprotegerin mitigates tail suspension-induced osteopenia, Bone research 2000; 26:443-9.
40. Bateman TA, Dunstan CR, Lacey DL,et al. Osteoprotegerin ameliorates sciatic nerve crush induced bone loss, Journal of Orthopedic research 2001; 19:518-23.
41. Lee SK, Lorenzo JA. Parathyroid hormone stimulates TRANCE and inhibits osteoprotegerin messenger ribonucleic acid expression in murine bone marrow cultures: correlation with osteoclast-like cell formation, Endocrinology 1999; 140:3552–61
42. Onyia JE, Miles RR, Yang X, et al. In vivo demonstration that parathyroid hormone 1-38 inhibits the expression of osteoprotegerin in bone with the kinetics of an immediate early gene. Journal of Bone Mineral Research 2000; 15:863-71
43. Locklin RM, Khosla S, Turner RT, et al. Mediators of the biphasic responses of bone to intermittent and continuously administered parathyroid hormone, Journal of Cellular Biochemistry 2003; 89:180-90.
44. Ziolkowska M, Kurowska M, Radzikowska A, et al. High levels of osteoprotegerin and soluble receptor activator of nuclear factor κB ligand in serum of rheumatoid arthritis patients and their normalization after anti-tumor necrosis factor α treatment, Arthritis Rheumatology 2002; 46:1744–53
45. Abeles AM, Pillinger MH. the role of the synovial fibroblast in rheumatoid arthritis: cartilage destruction and the regulation of matrix metalloproteinases, Bulletin of the NYU Hospital for Joint Diseases, 2006;64:20–24
46. Kim HR, Kim KW, Kim BM, et al. Reciprocal activation of CD4+ T cells and synovial fibroblasts by stromal cell-derived factor 1 promotes RANKL expression and osteoclastogenesis in rheumatoid arthritis, 2014; 66:538-48
47. Herzog CE. Overview of sarcomas in the adolescent and young adult population, Journal of Pediatric Hematology and Oncology 2005; 27:215–8.
48. Grimaud E, Soubigou L, Couillaud S, et al. Receptor activator of nuclear factor kappaB ligand (RANKL)/osteoprotegerin (OPG) ratio is increased in severe osteolysis, Americal journal of Pathology 2003; 163:2021–31
49. Lamoureux F, Richard P, Wittrant Y, et al. Therapeutic relevance of osteoprotegerin gene therapy in osteosarcoma: blockade of the vicious cycle between tumor cell proliferation and bone resorption. Cancer Research 2003; 67:7308–18
50. Pearse RN, Sordillo EM, Yaccoby S, et al. Multiple myeloma disrupts the TRANCE/osteoprotegerin cytokine axis to trigger bone destruction and promote tumor progression, Proceeding National academy of sciences 2001; 98:11581–6
51. Lewin J, Thomas D. Denosumab: a new treatment option for giant cell tumor of bone, Drugs Today 2013; 49:693-700
52. Whyte MP, Obrecht SE, Finnegan PM, et al. Osteoprotegerin deficiency and juvenile Paget’s disease, New England, Journal of Medicine 2002;347:175–84
53. Nakatsuka K, Nishizawa Y, Ralston SH. Phenotypic characterization of early onset Paget’s disease of bone caused by a 27-bp duplication in the TNFRSF11A gene, Journal of Bone Mineral Research 2003;18:1381–5
54. Whyte MP, Hughes AE. Expansile skeletal hyperphosphatasia is caused by a15-base pair tandem duplication in TNFRSF11A encoding RANK and is allelic to familial expansile osteolysis, Journal of Bone Mineral Research 2002; 17:26–29
55. Whyte MP, Reinus WR, Podgornik MN, et al. Familial expansile osteolysis in 5 generation American kindred, Medicine (Baltimore) 2002; 81:101 -21
56. Daroszewska A and Ralston SH. Mechanisms of disease: genetics of Paget's disease of bone and related disorders, National Clinical Practice of Rheumatololgy 2006; 2:270-7
57. Iotsova V, Caamano J, Loy J, et al. Osteopetrosis in mice lacking NF-κB1 and NF-κB2, Natural Medicine 1998; 3:1285–9
58. Kostenuik PJ, Nguyen HQ, McCabe J, et al. Denosumab, a fully human monoclonal antibody to RANKL, inhibits bone resorption and increases BMD in knock-in mice that express chimeric (murine/human) RANKL, Journal of Bone Mineral Research 2009; 24:182–95.
59. Peddi P, Lopez-Olivo MA, Pratt GF et al. Denosumab in patients with cancer and skeletal metastases: a systematic review and metaanalysis, Cancer Treatment Review 2013; 39:97–04.
60. Heath DJ, Vanderkerken K, Cheng X, et al. An Osteoprotegerin-like Peptidomimetic Inhibits Osteoclastic Bone Resorption and Osteolytic Bone Disease in Myeloma, Cancer Research 2007; 67
61. Kim H, Choi HK, Shin JH, et al., Selective inhibition of RANK blocks osteoclast maturation and function and prevents bone loss in mice, The Journal of Clinical Investigation 2009; 119: 4 
62. Téletchéa S, Stresing V, Hervouet S et al. Novel RANK Antagonists for the Treatment of Bone-Resorptive Disease: Theoretical Predictions and Experimental Validation, Journal of Bone Mineral Research 2014; 29:1466-77
63. Zhao Y, Jin M, Ma J, et al., Inhibition effect of enteropeptidase on RANKL-RANK signalling by cleavage of RANK, FEBS Letters 2013 587:2958-64.
64. Onyia JE, Rachelle J, Galvin RJS, et al. Novel and Selective Small Molecule Stimulators of Osteoprotegerin Expression Inhibit Bone Resorption, Journal of Pharmacology and Experimental Therapeutics 2010; 309:369–79
65. Naidu VG, Dinesh KR, Thwin MM et al. RANKL targeted peptides inhibit osteoclastogenesis and attenuate adjuvant induced arthritis by inhibiting NF-κB activation and down regulating inflammatory cytokines, Chemico Biological Interaction 2013; 203:467-79
66. Ma R, Xu J, Dong B, et al. Inhibition of osteoclastogenesis by RNA interference targeting RANK, Musculoskeletal Disorders 2012; 13:154
67. Brennan TC, Rybchyn MS, Green W, et al. Osteoblasts play key roles in the mechanisms of action of strontium ranelate, British Journal of Pharmacology 2009; 157:1291–1300
68. Xiu Y, Xu H, Zhao C, et al. Chloroquine reduces osteoclastogenesis in murine osteoporosis by preventing TRAF3 degradation, Joural of Clinical Investigation 2014; 124:297–10
69. Ma X, Liu Y, Zhang Y et al. Jolkinolide B inhibits RANKL-induced osteoclastogenesis by suppressing the activation NF-κB and MAPK signaling pathways, Biochemical ad Biophysical Research Communication 2014; 445:282-8
70. Ha H, Shim K, Kim T, et al. Water Extract of Acer tegmentosum reduces bone destruction by inhibiting osteoclast differentiation and function, Vitamins and Molecules 2014; 19: 3940-54
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How to Cite
Sisay M, Abdela J, Molla Y. THE MOLECULAR TRIAD SYSTEM INVOLVING RANK/RANKL/OPG AS THERAPEUTIC TARGETS FOR METABOLIC BONE DISEASES. JDDT [Internet]. 15Nov.2016 [cited 28Oct.2020];6(6):31-9. Available from: