This Article Full Text Full Text (PDF) 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 Reprints, Permissions and Rights Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kearns, A. E. Articles by Kostenuik, P. J. Search for Related Content PubMed PubMed Citation Articles by Kearns, A. E. Articles by Kostenuik, P. J.

Receptor Activator of Nuclear Factor B Ligand and Osteoprotegerin Regulation of Bone Remodeling in Health and Disease

Endocrine Research Unit (A.E.K., S.K.), Mayo Clinic College of Medicine, Rochester, Minnesota 55905; and Metabolic Disorders Research (P.J.K.), Amgen Inc., Thousand Oaks, California 91320

Correspondence: Address all correspondence and requests for reprints to: Paul J. Kostenuik, Amgen Inc., 1 Amgen Center Drive, M/S 15-2-B, Thousand Oaks, California 91320. E-mail: paulk{at}amgen.com

Osteoclasts and osteoblasts dictate skeletal mass, structure, and strength via their respective roles in resorbing and forming bone. Bone remodeling is a spatially coordinated lifelong process whereby old bone is removed by osteoclasts and replaced by bone-forming osteoblasts. The refilling of resorption cavities is incomplete in many pathological states, which leads to a net loss of bone mass with each remodeling cycle. Postmenopausal osteoporosis and other conditions are associated with an increased rate of bone remodeling, which leads to accelerated bone loss and increased risk of fracture. Bone resorption is dependent on a cytokine known as RANKL (receptor activator of nuclear factor B ligand), a TNF family member that is essential for osteoclast formation, activity, and survival in normal and pathological states of bone remodeling. The catabolic effects of RANKL are prevented by osteoprotegerin (OPG), a TNF receptor family member that binds RANKL and thereby prevents activation of its single cognate receptor called RANK. Osteoclast activity is likely to depend, at least in part, on the relative balance of RANKL and OPG. Studies in numerous animal models of bone disease show that RANKL inhibition leads to marked suppression of bone resorption and increases in cortical and cancellous bone volume, density, and strength. RANKL inhibitors also prevent focal bone loss that occurs in animal models of rheumatoid arthritis and bone metastasis. Clinical trials are exploring the effects of denosumab, a fully human anti-RANKL antibody, on bone loss in patients with osteoporosis, bone metastasis, myeloma, and rheumatoid arthritis.

This article has been cited by other articles:

				S. Kwan Tat, N. Amiable, J.-P. Pelletier, C. Boileau, D. Lajeunesse, N. Duval, and J. Martel-Pelletier Modulation of OPG, RANK and RANKL by human chondrocytes and their implication during osteoarthritis Rheumatology, December 1, 2009; 48(12): 1482 - 1490. [Abstract] [Full Text] [PDF]

				M. Baud'huin, L. Duplomb, S. Teletchea, C. Charrier, M. Maillasson, M. Fouassier, and D. Heymann Factor VIII-von Willebrand Factor Complex Inhibits Osteoclastogenesis and Controls Cell Survival J. Biol. Chem., November 13, 2009; 284(46): 31704 - 31713. [Abstract] [Full Text] [PDF]

				J. M. Zmuda Identification of Osteoporosis Risk Genes: The Tip of the Iceberg Ann Intern Med, October 20, 2009; 151(8): 581 - 582. [Full Text] [PDF]

				E. M. Lewiecki Denosumab in postmenopausal osteoporosis: what the clinician needs to know Therapeutic Advances in Musculoskeletal Diseases, October 1, 2009; 1(1): 13 - 26. [Abstract] [PDF]

				H. H. Conaway, E. Persson, M. Halen, S. Granholm, O. Svensson, U. Pettersson, A. Lie, and U. H. Lerner Retinoids inhibit differentiation of hematopoetic osteoclast progenitors FASEB J, October 1, 2009; 23(10): 3526 - 3538. [Abstract] [Full Text] [PDF]

				J. H. Kim, H. M. Jin, K. Kim, I. Song, B. U. Youn, K. Matsuo, and N. Kim The Mechanism of Osteoclast Differentiation Induced by IL-1 J. Immunol., August 1, 2009; 183(3): 1862 - 1870. [Abstract] [Full Text] [PDF]

				M. Ohishi, R. Chiusaroli, M. Ominsky, F. Asuncion, C. Thomas, R. Khatri, P. Kostenuik, and E. Schipani Osteoprotegerin Abrogated Cortical Porosity and Bone Marrow Fibrosis in a Mouse Model of Constitutive Activation of the PTH/PTHrP Receptor Am. J. Pathol., June 1, 2009; 174(6): 2160 - 2171. [Abstract] [Full Text] [PDF]

				T. Kim, K. Kim, S. H. Lee, H.-S. So, J. Lee, N. Kim, and Y. Choi Identification of LRRc17 as a Negative Regulator of Receptor Activator of NF-{kappa}B Ligand (RANKL)-induced Osteoclast Differentiation J. Biol. Chem., May 29, 2009; 284(22): 15308 - 15316. [Abstract] [Full Text] [PDF]

				C. Galli, Q. Fu, W. Wang, B. R. Olsen, S. C. Manolagas, R. L. Jilka, and C. A. O'Brien Commitment to the Osteoblast Lineage Is Not Required for RANKL Gene Expression J. Biol. Chem., May 8, 2009; 284(19): 12654 - 12662. [Abstract] [Full Text] [PDF]

				S. Vignot and D. Khayat A Step in the Journey of Denosumab From Bone-Targeted Therapy to Seed- and Soil-Targeted Therapy J. Clin. Oncol., April 1, 2009; 27(10): 1534 - 1536. [Full Text] [PDF]

				S. Ferrari-Lacraz and S. Ferrari Effects of RANKL Inhibition on Inflammation and Immunity IBMS BoneKEy, March 1, 2009; 6(3): 116 - 126. [Abstract] [Full Text] [PDF]

				J. N. Hirschhorn and L. Gennari Bona Fide Genetic Associations with Bone Mineral Density N. Engl. J. Med., May 29, 2008; 358(22): 2403 - 2405. [Full Text] [PDF]

				U. Styrkarsdottir, B. V. Halldorsson, S. Gretarsdottir, D. F. Gudbjartsson, G. B. Walters, T. Ingvarsson, T. Jonsdottir, J. Saemundsdottir, J. R. Center, T. V. Nguyen, et al. Multiple Genetic Loci for Bone Mineral Density and Fractures N. Engl. J. Med., May 29, 2008; 358(22): 2355 - 2365. [Abstract] [Full Text] [PDF]