This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Khosla, S. Search for Related Content PubMed PubMed Citation Articles by Khosla, S.

Minireview: The OPG/RANKL/RANK System

Endocrine Research Unit, Division of Endocrinology, Metabolism, and Nutrition, Mayo Clinic and Foundation, Rochester, Minnesota 55905

Address all correspondence and requests for reprints to: Sundeep Khosla, M.D., Mayo Clinic, 200 First Street SW, 5-194 Joseph, Rochester, Minnesota 55905. E-mail: khosla.sundeep{at}mayo.edu

The identification of the OPG/RANKL/RANK system as the dominant, final mediator of osteoclastogenesis represents a major advance in bone biology. It ended a long-standing search for the specific factor produced by preosteoblastic/stromal cells that was both necessary and sufficient for osteoclast development. The initial cloning and characterization of OPG as a soluble, decoy receptor belonging to the TNF receptor superfamily was the first step that eventually led to an unraveling of this system. Soon thereafter, the molecule blocked by OPG, initially called OPG-ligand/osteoclast differentiating factor (ODF) and subsequently RANKL, was identified as the key mediator of osteoclastogenesis in both a membrane-bound form expressed on preosteoblastic/stromal cells as well as a soluble form. RANKL, in turn, was shown to bind its receptor, RANK, on osteoclast lineage cells. The decisive role played by these factors in regulating bone metabolism was demonstrated by the findings of extremes of skeletal phenotypes (osteoporosis vs. osteopetrosis) in mice with altered expression of these molecules. Over the past several years, work has focused on identifying the factors regulating this system, the signaling mechanisms involved in the RANKL/RANK pathway, and finally, potential alterations in this system in metabolic bone disorders, from the extremely common (i.e. postmenopausal osteoporosis) to the rare (i.e. familial expansile osteolysis).

This article has been cited by other articles:

				L. Pederson, M. Ruan, J. J. Westendorf, S. Khosla, and M. J. Oursler Regulation of bone formation by osteoclasts involves Wnt/BMP signaling and the chemokine sphingosine-1-phosphate PNAS, December 30, 2008; 105(52): 20764 - 20769. [Abstract] [Full Text] [PDF]

				J. Cornish, A. MacGibbon, J.-M. Lin, M. Watson, K. E. Callon, P. C. Tong, J. E. Dunford, Y. van der Does, G. A. Williams, A. B. Grey, et al. Modulation of Osteoclastogenesis by Fatty Acids Endocrinology, November 1, 2008; 149(11): 5688 - 5695. [Abstract] [Full Text] [PDF]

				A. I. Idris, A. Sophocleous, E. Landao-Bassonga, R. J. van't Hof, and S. H. Ralston Regulation of Bone Mass, Osteoclast Function, and Ovariectomy-Induced Bone Loss by the Type 2 Cannabinoid Receptor Endocrinology, November 1, 2008; 149(11): 5619 - 5626. [Abstract] [Full Text] [PDF]

				D. E. Wallis, S. Penckofer, and G. W. Sizemore The "Sunshine Deficit" and Cardiovascular Disease Circulation, September 30, 2008; 118(14): 1476 - 1485. [Full Text] [PDF]

				E. J. Samelson, K. E. Broe, S. Demissie, T. J. Beck, D. Karasik, S. Kathiresan, and D. P. Kiel Increased Plasma Osteoprotegerin Concentrations Are Associated with Indices of Bone Strength of the Hip J. Clin. Endocrinol. Metab., May 1, 2008; 93(5): 1789 - 1795. [Abstract] [Full Text] [PDF]

				S. P. Moffett, J. I. Oakley, J. A. Cauley, L. Y. Lui, K. E. Ensrud, B. C. Taylor, T. A. Hillier, M. C. Hochberg, J. Li, S. Cayabyab, et al. Osteoprotegerin Lys3Asn Polymorphism and the Risk of Fracture in Older Women J. Clin. Endocrinol. Metab., May 1, 2008; 93(5): 2002 - 2008. [Abstract] [Full Text] [PDF]

				H. R. Johansson, R. Skripitz, and P. Aspenberg Bisphosphonates can block the deterioration in implant fixation after withdrawal of intermittent doses of parathyroid hormone J Bone Joint Surg Br, March 1, 2008; 90-B(3): 400 - 404. [Abstract] [Full Text] [PDF]

				X. Li, L. Qin, M. Bergenstock, L. M. Bevelock, D. V. Novack, and N. C. Partridge Parathyroid Hormone Stimulates Osteoblastic Expression of MCP-1 to Recruit and Increase the Fusion of Pre/Osteoclasts J. Biol. Chem., November 9, 2007; 282(45): 33098 - 33106. [Abstract] [Full Text] [PDF]

				S. Ferrari Are Osteoclasts Necessary for PTH Anabolism? A Reappraisal from Osteoprotegerin Studies IBMS BoneKEy, October 1, 2007; 4(10): 278 - 281. [Full Text] [PDF]

				C.H. Li and S. Amar Inhibition of SFRP1 Reduces Severity of Periodontitis J. Dent. Res., September 1, 2007; 86(9): 873 - 877. [Abstract] [Full Text] [PDF]

				C.H. Li and S. Amar Inhibition of SFRP1 Reduces Severity of Periodontitis Journal of Dental Research, September 1, 2007; 86(9): 873 - 877. [Abstract] [Full Text] [PDF]

				M. Misra, K. K. Miller, J. Cord, R. Prabhakaran, D. B. Herzog, M. Goldstein, D. K. Katzman, and A. Klibanski Relationships between Serum Adipokines, Insulin Levels, and Bone Density in Girls with Anorexia Nervosa J. Clin. Endocrinol. Metab., June 1, 2007; 92(6): 2046 - 2052. [Abstract] [Full Text] [PDF]

				R. Baron and G. Rawadi Targeting the Wnt/{beta}-Catenin Pathway to Regulate Bone Formation in the Adult Skeleton Endocrinology, June 1, 2007; 148(6): 2635 - 2643. [Abstract] [Full Text] [PDF]

				A. Stern, G. A Laughlin, J. Bergstrom, and E. Barrett-Connor The sex-specific association of serum osteoprotegerin and receptor activator of nuclear factor {kappa}B legend with bone mineral density in older adults: the Rancho Bernardo Study Eur. J. Endocrinol., May 1, 2007; 156(5): 555 - 562. [Abstract] [Full Text] [PDF]

				Y. Li, G. Toraldo, A. Li, X. Yang, H. Zhang, W.-P. Qian, and M. N. Weitzmann B cells and T cells are critical for the preservation of bone homeostasis and attainment of peak bone mass in vivo Blood, May 1, 2007; 109(9): 3839 - 3848. [Abstract] [Full Text] [PDF]

				S. Ferrari Single Gene Mutations and Variations Affecting Bone Turnover and Strength: a Selective 2006 Update IBMS BoneKEy, December 1, 2006; 3(12): 11 - 29. [Abstract] [Full Text] [PDF]

				C. Alewine, O. Olsen, J. B. Wade, and P. A. Welling TIP-1 Has PDZ Scaffold Antagonist Activity Mol. Biol. Cell, October 1, 2006; 17(10): 4200 - 4211. [Abstract] [Full Text] [PDF]

				B. J. Bennett, M. Scatena, E. A. Kirk, M. Rattazzi, R. M. Varon, M. Averill, S. M. Schwartz, C. M. Giachelli, and M. E. Rosenfeld Osteoprotegerin Inactivation Accelerates Advanced Atherosclerotic Lesion Progression and Calcification in Older ApoE-/- Mice Arterioscler. Thromb. Vasc. Biol., September 1, 2006; 26(9): 2117 - 2124. [Abstract] [Full Text] [PDF]

				D. Granchi, A. Pellacani, M. Spina, E. Cenni, L. M. Savarino, N. Baldini, and A. Giunti Serum Levels of Osteoprotegerin and Receptor Activator of Nuclear Factor-{kappa}B Ligand as Markers of Periprosthetic Osteolysis J. Bone Joint Surg. Am., July 1, 2006; 88(7): 1501 - 1509. [Abstract] [Full Text] [PDF]

				N. Rasheed, X. Wang, Q.-T. Niu, J. Yeh, and B. Li Atm-deficient mice: an osteoporosis model with defective osteoblast differentiation and increased osteoclastogenesis Hum. Mol. Genet., June 15, 2006; 15(12): 1938 - 1948. [Abstract] [Full Text] [PDF]

				M. S. Bendre, A. G. Margulies, B. Walser, N. S. Akel, S. Bhattacharrya, R. A. Skinner, F. Swain, V. Ramani, K. S. Mohammad, L. L. Wessner, et al. Tumor-Derived Interleukin-8 Stimulates Osteolysis Independent of the Receptor Activator of Nuclear Factor-{kappa}B Ligand Pathway Cancer Res., December 1, 2005; 65(23): 11001 - 11009. [Abstract] [Full Text] [PDF]

				A. Rogers and R. Eastell Circulating Osteoprotegerin and Receptor Activator for Nuclear Factor {kappa}B Ligand: Clinical Utility in Metabolic Bone Disease Assessment J. Clin. Endocrinol. Metab., November 1, 2005; 90(11): 6323 - 6331. [Abstract] [Full Text] [PDF]

				C. A. O'Brien, R. L. Jilka, Q. Fu, S. Stewart, R. S. Weinstein, and S. C. Manolagas IL-6 is not required for parathyroid hormone stimulation of RANKL expression, osteoclast formation, and bone loss in mice Am J Physiol Endocrinol Metab, November 1, 2005; 289(5): E784 - E793. [Abstract] [Full Text] [PDF]

				M. F. Holick The Vitamin D Epidemic and its Health Consequences J. Nutr., November 1, 2005; 135(11): 2739S - 2748S. [Abstract] [Full Text] [PDF]

				A. S. Dusso, A. J. Brown, and E. Slatopolsky Vitamin D Am J Physiol Renal Physiol, July 1, 2005; 289(1): F8 - F28. [Abstract] [Full Text] [PDF]

				D. Hamerman Osteoporosis and atherosclerosis: biological linkages and the emergence of dual-purpose therapies QJM, July 1, 2005; 98(7): 467 - 484. [Abstract] [Full Text] [PDF]

				P. Valverde, T. Kawai, and M.A. Taubman Potassium Channel-blockers as Therapeutic Agents to Interfere with Bone Resorption of Periodontal Disease J. Dent. Res., June 1, 2005; 84(6): 488 - 499. [Abstract] [Full Text] [PDF]

				P. Valverde, T. Kawai, and M.A. Taubman Potassium Channel-blockers as Therapeutic Agents to Interfere with Bone Resorption of Periodontal Disease Journal of Dental Research, June 1, 2005; 84(6): 488 - 499. [Abstract] [Full Text] [PDF]

				M. Subramaniam, G. Gorny, S. A. Johnsen, D. G. Monroe, G. L. Evans, D. G. Fraser, D. J. Rickard, K. Rasmussen, J. M. A. van Deursen, R. T. Turner, et al. TIEG1 Null Mouse-Derived Osteoblasts Are Defective in Mineralization and in Support of Osteoclast Differentiation In Vitro Mol. Cell. Biol., February 1, 2005; 25(3): 1191 - 1199. [Abstract] [Full Text] [PDF]

				M. F Holick Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease Am. J. Clinical Nutrition, December 1, 2004; 80(6): 1678S - 1688S. [Abstract] [Full Text] [PDF]

				Z de Jong, M Munneke, A H Zwinderman, H M Kroon, K H Ronday, W F Lems, B A C Dijkmans, F C Breedveld, T P M Vliet Vlieland, J M W Hazes, et al. Long term high intensity exercise and damage of small joints in rheumatoid arthritis Ann Rheum Dis, November 1, 2004; 63(11): 1399 - 1405. [Abstract] [Full Text] [PDF]

				A. K. Bengtsson, E. J. Ryan, D. Giordano, D. M. Magaletti, and E. A. Clark 17{beta}-Estradiol (E2) modulates cytokine and chemokine expression in human monocyte-derived dendritic cells Blood, September 1, 2004; 104(5): 1404 - 1410. [Abstract] [Full Text] [PDF]

				M. B. Leonard, H. I. Feldman, J. Shults, B. S. Zemel, B. J. Foster, and V. A. Stallings Long-Term, High-Dose Glucocorticoids and Bone Mineral Content in Childhood Glucocorticoid-Sensitive Nephrotic Syndrome N. Engl. J. Med., August 26, 2004; 351(9): 868 - 875. [Abstract] [Full Text] [PDF]

				T. M. Doherty, L. A. Fitzpatrick, D. Inoue, J.-H. Qiao, M. C. Fishbein, R. C. Detrano, P. K. Shah, and T. B. Rajavashisth Molecular, Endocrine, and Genetic Mechanisms of Arterial Calcification Endocr. Rev., August 1, 2004; 25(4): 629 - 672. [Abstract] [Full Text] [PDF]

				E. C. Buxton, W. Yao, and N. E. Lane Changes in Serum Receptor Activator of Nuclear Factor-{kappa}B Ligand, Osteoprotegerin, and Interleukin-6 Levels in Patients with Glucocorticoid-Induced Osteoporosis Treated with Human Parathyroid Hormone (1-34) J. Clin. Endocrinol. Metab., July 1, 2004; 89(7): 3332 - 3336. [Abstract] [Full Text] [PDF]

				M. Delgado, D. Pozo, and D. Ganea The Significance of Vasoactive Intestinal Peptide in Immunomodulation Pharmacol. Rev., June 1, 2004; 56(2): 249 - 290. [Abstract] [Full Text] [PDF]

				G Livshits, I Pantsulaia, S Trofimov, and E Kobyliansky Genetic influences on the circulating cytokines involved in osteoclastogenesis J. Med. Genet., June 1, 2004; 41(6): e76 - e76. [Full Text] [PDF]

				R. Vattikuti and D. A. Towler Osteogenic regulation of vascular calcification: an early perspective Am J Physiol Endocrinol Metab, May 1, 2004; 286(5): E686 - E696. [Abstract] [Full Text] [PDF]

				X. Cheng, M. Kinosaki, M. Takami, Y. Choi, H. Zhang, and R. Murali Disabling of Receptor Activator of Nuclear Factor-{kappa}B (RANK) Receptor Complex by Novel Osteoprotegerin-like Peptidomimetics Restores Bone Loss in Vivo J. Biol. Chem., February 27, 2004; 279(9): 8269 - 8277. [Abstract] [Full Text] [PDF]

				A. Crisafulli, D. Altavilla, G. Squadrito, A. Romeo, E. B. Adamo, R. Marini, M. A. Inferrera, H. Marini, A. Bitto, R. D'anna, et al. Effects of the Phytoestrogen Genistein on the Circulating Soluble Receptor Activator of Nuclear Factor {kappa}B Ligand-Osteoprotegerin System in Early Postmenopausal Women J. Clin. Endocrinol. Metab., January 1, 2004; 89(1): 188 - 192. [Abstract] [Full Text] [PDF]

				S. Srivastava, M. Matsuda, Z. Hou, J. P. Bailey, R. Kitazawa, M. P. Herbst, and N. D. Horseman Receptor Activator of NF-{kappa}B Ligand Induction via Jak2 and Stat5a in Mammary Epithelial Cells J. Biol. Chem., November 14, 2003; 278(46): 46171 - 46178. [Abstract] [Full Text] [PDF]

				K. E. Naylor, A. Rogers, R. B. Fraser, V. Hall, R. Eastell, and A. Blumsohn Serum Osteoprotegerin as a Determinant of Bone Metabolism in a Longitudinal Study of Human Pregnancy and Lactation J. Clin. Endocrinol. Metab., November 1, 2003; 88(11): 5361 - 5365. [Abstract] [Full Text] [PDF]

				T. M. Doherty, K. Asotra, L. A. Fitzpatrick, J.-H. Qiao, D. J. Wilkin, R. C. Detrano, C. R. Dunstan, P. K. Shah, and T. B. Rajavashisth Calcification in atherosclerosis: Bone biology and chronic inflammation at the arterial crossroads PNAS, September 30, 2003; 100(20): 11201 - 11206. [Abstract] [Full Text] [PDF]

				V. Viereck, C. Grundker, S. Blaschke, B. Niederkleine, H. Siggelkow, K.-H. Frosch, D. Raddatz, G. Emons, and L. C. Hofbauer Raloxifene Concurrently Stimulates Osteoprotegerin and Inhibits Interleukin-6 Production by Human Trabecular Osteoblasts J. Clin. Endocrinol. Metab., September 1, 2003; 88(9): 4206 - 4213. [Abstract] [Full Text] [PDF]

				M. Misra, L. A. Soyka, K. K. Miller, D. B. Herzog, S. Grinspoon, D. de Chen, G. Neubauer, and A. Klibanski Serum Osteoprotegerin in Adolescent Girls with Anorexia Nervosa J. Clin. Endocrinol. Metab., August 1, 2003; 88(8): 3816 - 3822. [Abstract] [Full Text] [PDF]

				R. Kawaida, T. Ohtsuka, J. Okutsu, T. Takahashi, Y. Kadono, H. Oda, A. Hikita, K. Nakamura, S. Tanaka, and H. Furukawa Jun Dimerization Protein 2 (JDP2), a Member of the AP-1 Family of Transcription Factor, Mediates Osteoclast Differentiation Induced by RANKL J. Exp. Med., April 21, 2003; 197(8): 1029 - 1035. [Abstract] [Full Text] [PDF]

				U. Heider, C. Langelotz, C. Jakob, I. Zavrski, C. Fleissner, J. Eucker, K. Possinger, L. C. Hofbauer, and O. Sezer Expression of Receptor Activator of Nuclear Factor {kappa}B Ligand on Bone Marrow Plasma Cells Correlates with Osteolytic Bone Disease in Patients with Multiple Myeloma Clin. Cancer Res., April 1, 2003; 9(4): 1436 - 1440. [Abstract] [Full Text] [PDF]

				O. Sezer, U. Heider, I. Zavrski, C. A. Kuhne, and L. C. Hofbauer RANK ligand and osteoprotegerin in myeloma bone disease Blood, March 15, 2003; 101(6): 2094 - 2098. [Abstract] [Full Text] [PDF]

				T. Sugatani, U. Alvarez, and K. A. Hruska PTEN Regulates RANKL- and Osteopontin-stimulated Signal Transduction during Osteoclast Differentiation and Cell Motility J. Biol. Chem., February 7, 2003; 278(7): 5001 - 5008. [Abstract] [Full Text] [PDF]

				G. Toraldo, C. Roggia, W.-P. Qian, R. Pacifici, and M. N. Weitzmann IL-7 induces bone loss in vivo by induction of receptor activator of nuclear factor kappa B ligand and tumor necrosis factor alpha from T cells PNAS, January 7, 2003; 100(1): 125 - 130. [Abstract] [Full Text] [PDF]

				N. Giuliani, S. Colla, R. Sala, M. Moroni, M. Lazzaretti, S. La Monica, S. Bonomini, M. Hojden, G. Sammarelli, S. Barille, et al. Human myeloma cells stimulate the receptor activator of nuclear factor-kappa B ligand (RANKL) in T lymphocytes: a potential role in multiple myeloma bone disease Blood, December 15, 2002; 100(13): 4615 - 4621. [Abstract] [Full Text] [PDF]

				Q. Fu, R. L. Jilka, S. C. Manolagas, and C. A. O'Brien Parathyroid Hormone Stimulates Receptor Activator of NFkappa B Ligand and Inhibits Osteoprotegerin Expression via Protein Kinase A Activation of cAMP-response Element-binding Protein J. Biol. Chem., December 6, 2002; 277(50): 48868 - 48875. [Abstract] [Full Text] [PDF]

				U. M. Liegibel, U. Sommer, P. Tomakidi, U. Hilscher, L. van den Heuvel, R. Pirzer, J. Hillmeier, P. Nawroth, and C. Kasperk Concerted Action of Androgens and Mechanical Strain Shifts Bone Metabolism from High Turnover into an Osteoanabolic Mode J. Exp. Med., November 18, 2002; 196(10): 1387 - 1392. [Abstract] [Full Text] [PDF]

				T. Cundy, M. Hegde, D. Naot, B. Chong, A. King, R. Wallace, J. Mulley, D. R. Love, J. Seidel, M. Fawkner, et al. A mutation in the gene TNFRSF11B encoding osteoprotegerin causes an idiopathic hyperphosphatasia phenotype Hum. Mol. Genet., September 1, 2002; 11(18): 2119 - 2127. [Abstract] [Full Text] [PDF]

				M. J. Silva and L. J. Sandell What's New in Orthopaedic Research J. Bone Joint Surg. Am., August 12, 2002; 84(8): 1490 - 1496. [Full Text] [PDF]

				M. P. Whyte, S. E. Obrecht, P. M. Finnegan, J. L. Jones, M. N. Podgornik, W. H. McAlister, and S. Mumm Osteoprotegerin Deficiency and Juvenile Paget's Disease N. Engl. J. Med., July 18, 2002; 347(3): 175 - 184. [Abstract] [Full Text] [PDF]

				D. Cappellen, N.-H. Luong-Nguyen, S. Bongiovanni, O. Grenet, C. Wanke, and 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., June 7, 2002; 277(24): 21971 - 21982. [Abstract] [Full Text] [PDF]

				T. M. DOHERTY, H. UZUI, L. A. FITZPATRICK, P. V. TRIPATHI, C. R. DUNSTAN, K. ASOTRA, and T. B. RAJAVASHISTH Rationale for the role of osteoclast-like cells in arterial calcification FASEB J, April 1, 2002; 16(6): 577 - 582. [Abstract] [Full Text] [PDF]