Osteoprotegerin:​ a novel secreted protein involved in the regulation of bone density

Simonet, W. S.; Lacey, D. L.; Dunstan, C. R.; Kelley, M.; Chang, M.-S.; Lüthy, R.; Nguyen, H. Q.; Wooden, S.; Bennett, L.; Boone, T.; Shimamoto, G.; DeRose, M.; Elliott, R.; Colombero, A.; Tan, H.-L.; Trail, G.; Sullivan, J.; Davy, E.; Bucay, N.; Renshaw-Gegg, L.; Hughes, T. M.; Hill, D.; Pattison, W.; Campbell, P.; Sander, S.; Van, G.; Tarpley, J.; Derby, P.; Lee, R.; Boyle, W. J.

Affiliations

¹Department of Molecular Genetics, Amgen Inc., 1840 DeHavilland Drive, Thousand Oaks, California 91320

²Department of Pathology, Amgen Inc., 1840 DeHavilland Drive, Thousand Oaks, California 91320

³Department of Protein Chemistry, Amgen Inc., 1840 DeHavilland Drive, Thousand Oaks, California 91320

⁴Department of Computational Biology, Amgen Inc., 1840 DeHavilland Drive, Thousand Oaks, California 91320

⁵Department of Mammalian Cell Molecular Biology, Amgen Inc., 1840 DeHavilland Drive, Thousand Oaks, California 91320

⁶Department of Immunology, Amgen Inc., 1840 DeHavilland Drive, Thousand Oaks, California 91320

⁷Department of Process Science, Amgen Inc., 1840 DeHavilland Drive, Thousand Oaks, California 91320

⁸Department of Cell Biology, Amgen Inc., 1840 DeHavilland Drive, Thousand Oaks, California 91320

⁹Department of Bacterial Expression, Amgen Inc., 1840 DeHavilland Drive, Thousand Oaks, California 91320

¹⁰Department of Protein Structure, Amgen Inc., 1840 DeHavilland Drive, Thousand Oaks, California 91320

Abstract

A novel secreted glycoprotein that regulates bone resorption has been identified. The protein, termed Osteoprotegerin (OPG), is a novel member of the TNF receptor superfamily. In vivo, hepatic expression of OPG in transgenic mice results in a profound yet nonlethal osteopetrosis, coincident with a decrease in later stages of osteoclast differentiation. These same effects are observed upon administration of recombinant OPG into normal mice. In vitro, osteoclast differentiation from precursor cells is blocked in a dose-dependent manner by recombinant OPG. Furthermore, OPG blocks ovariectomy-associated bone loss in rats. These data show that OPG can act as a soluble factor in the regulation of bone mass and imply a utility for OPG in the treatment of osteoporosis associated with increased osteoclast activity.

Links

DOI: 10.1016/S0092-8674(00)80209-3

PubMed: 9108485

WoS: A1997WU88800017

History

Received: 1997-02-13

Revised: 1997-04-18

Cited Works (2)

Year	Entry
1981	Rodan GA, Martin TJ. Role of osteoblasts in hormonal control of bone resorption: a hypothesis. Calcif Tiss Int. December 1981;33(1):349-351.
1990	Yoshida H, Hayashi S-I, Kunisada T, Ogawa M, Nishikawa S, Okamura H, Sudo T, Shultz LD, Nishikawa S-I. The murine mutation osteopetrosis is in the coding region of the macrophage colony stimulating factor gene. Nature. May 31, 1990;345(6274):442-444.

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Year	Entry
2006	Hadjidakis DJ, Androulakis II. Bone remodeling. Annals NY Acad Sci. December 2006;1092(1):385-396.
2006	Robling AG, Castillo AB, Turner CH. Biomechanical and molecular regulation of bone remodeling. Annu Rev Biomed Eng. 2006;8:455-498.
2011	Feng X, McDonald JM. Disorders of bone remodeling. Annu Rev Pathol. 2011;6:121-145.
2008	Miller PD, Bolognese MA, Lewiecki EM, McClung MR, Ding B, Austin M, Liu Y, San Martin J; AMG 162 Bone Loss Study Group. Effect of denosumab on bone density and turnover in postmenopausal women with low bone mass after long-term continued, discontinued, and restarting of therapy: a randomized blinded phase 2 clinical trial. Bone. August 2008;43(2):222-229.
2020	Sugisaki R, Miyamoto Y, Yoshimura K, Sasa K, Kaneko K, Tanaka M, Itose M, Inoue S, Baba K, Shirota T, Chikazu D, Kamijo R. Possible involvement of elastase in enhanced osteoclast differentiation by neutrophils through degradation of osteoprotegerin. Bone. March 2020;132:115216.
2020	Moura SR, Bras JP, Freitas J, Osório H, Barbosa MA, Santos SG, Almeida MI. miR-99a in bone homeostasis: regulating osteogenic lineage commitment and osteoclast differentiation. Bone. May 2020;134:115303.
2020	Yu J, Canalis E. Notch and the regulation of osteoclast differentiation and function. Bone. September 2020;138:115474.
2020	Santos MRG, Queiroz-Junior CM, Madeira MFM, Machado FS. Suppressors of cytokine signaling (SOCS) proteins in inflammatory bone disorders. Bone. November 2020;140:115538.
2021	Weivoda MM, Lee S-K, Monroe DG. MiRNAs in osteoclast biology. Bone. February 2021;143:115757.
2021	Kao S-Y, Katsumi S, Han D, Bizaki-Vallaskangas AJ, Vasilijic S, Landegger LD, Kristiansen AG, McKenna MJ, Stankovic KM. Postnatal expression and possible function of RANK and RANKL in the murine inner ear. Bone. April 2021;145:115837.
2021	Carrillo-López N, Martínez-Arias L, Fernández-Villabrille S, Ruiz-Torres MP, Dusso A, Cannata-Andía JB, Naves-Díaz M, Panizo S; European Renal Osteodystrophy (EUROD) Workgroup. Role of the RANK/RANKL/OPG and Wnt/β-catenin systems in CKD bone and cardiovascular disorders. Calcif Tiss Int. April 2021;108(4):439-451.
1998	Lacey DL, Timms E, Tan H-L, Kelley MJ, Dunstan CR, Burgess T, Elliott R, Colombero A, Elliott G, Scully S, Hsu H, Sullivan J, Hawkins N, Davy E, Capparelli C, Eli A, Qian Y-X, Kaufman S, Sarosi I, Shalhoub V, Senaldi G, Guo J, Delaney J, Boyle WJ. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell. April 17, 1998;93(2):165-176.
1999	Suda T, Takahashi N, Udagawa N, Jimi E, Gillespie MT, Martin TJ. Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families. Endocr Rev. June 1999;20(3):345-357.
2000	Manolagas SC. Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis. Endocr Rev. April 2000;21(2):115-137.
2002	Zhao S, Kato Y, Zhang Y, Harris S, Ahuja SS, Bonewald LF. MLO‐Y4 osteocyte‐like cells support osteoclast formation and activation. J Bone Miner Res. November 2002;17(11):2068-2079.
2020	Henaff CL, Ricarte F, Finnie B, He Z, Johnson J, Warshaw J, Kolupaeva V, Partridge NC. Abaloparatide at the same dose has the same effects on bone as PTH (1‐34) in mice. J Bone Miner Res. April 2020;35(4):714-724.
2022	Chlebek C, Moore JA, Ross FP, van der Meulen MCH. Molecular identification of spatially distinct anabolic responses to mechanical loading in murine cortical bone. J Bone Miner Res. November 2022;37(11):2277-2287.
2003	Eghbali-Fatourechi G, Khosla S, Sanyal A, Boyle WJ, Lacey DL, Riggs BL. Role of RANK ligand in mediating increased bone resorption in early postmenopausal women. J Clin Invest. April 2003;111(8):1221-1230.
2002	Nakamura H, Tsuji T, Hirata A, Yamamoto T. Localization of osteoprotegerin (OPG) on bone surfaces and cement lines in rat tibia. J Histochem Cytochem. 2002;50(7):945-953.
2022	Becerikli M, Reinkemeier F, Dadras M, Wallner C, Wagner JM, Drysch M, Sogorski A, von Glinski M, Lehnhardt M, Hahn SA, Behr B. TGF-beta pathway inhibition as the therapeutic acceleration of diabetic bone regeneration. J Orthop Res. August 2022;40(8):1810-1826.
2002	Seeman E. Pathogenesis of bone fragility in women and men. Lancet. May 25, 2002;359(9320):1841-1850.
2011	Rachner TD, Khosla S, Hofbauer LC. Osteoporosis: now and the future. Lancet. April 9, 2011;377(9773):1276-1287.
2017	Khosla S, Hofbauer LC. Osteoporosis treatment: recent developments and ongoing challenges. Lancet Diabetes Endocrinol. November 2017;5(11):898-907.
2003	Teitelbaum SL, Ross FP. Genetic regulation of osteoclast development and function. Nat Rev Genet. August 2003;4(8):638-649.
1999	Kong Y-Y, Yoshida H, Sarosi I, Tan H-L, Timms E, Capparelli C, Morony S, Oliveira-dos-Santos AJ, Van G, Itie A, Khoo W, Wakeham A, Dunstan CR, Lacey DL, Mak TW, Boyle WJ, Penninger JM. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature. January 28, 1999;397(6717):315-323.
1999	Kong Y-Y, Feige U, Sarosi I, Bolon B, Tafuri A, Morony S, Capparelli C, Li J, Elliott R, McCabe S, Wong T, Campagnuolo G, Moran E, Bogoch ER, Van G, Nguyen LT, Ohashi PS, Lacey DL, Fish E, Boyle WJ, Penninger JM. Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature. November 18, 1999;402(6759):304-309.
2003	Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature. May 15, 2003;423(6937):337-342.
2004	Roodman GD. Mechanisms of bone metastasis. NEJM. April 15, 2004;350(16):1655-1664.
2007	Yuan Y. The Differential Effects of Two Critical Osteoclastogenesis Stimulating Factors on Bone Biomechanics [PhD thesis]. Clemson, SC: Clemson University; May 2007.
2008	Willey JS. Radiation-Induced Osteoporosis: Bone Quantity, Architecture, and Increased Resorption Following Exposure to Ionizing Radiation [PhD thesis]. Clemson, SC: Clemson University; May 2008.
2017	Bowman LC. Whole Body Irradiation and Degradation of Structural and Functional Properties of Mouse Bone: X-Rays, Protons, and Heavy Ions [PhD thesis]. Clemson, SC: Clemson University; December 2017.
1998	Bateman TA. Cytokine Therapies for Short-Term Disuse Osteopenia Models in Murines [PhD thesis]. University of Colorado; 1998.
2020	Robinson ST. Bone Mechanobiology of Modeling and Remodeling and the Effect of Hematopoietic Lineage Cells [PhD thesis]. Columbia University; 2020.
2012	Slyfield CR Jr. The Biomechanics of Bone Turnover [PhD thesis]. Ithaca, NY: Cornell University; January 2012.
2022	Chlebek C. Identification of Novel Cellular Pathways Involved in Bone Mechanotransduction Using Transcriptomics [PhD thesis]. Ithaca, NY: Cornell University; May 2022.
2005	Murray AW. Fracture Healing in Osteopenic Bone and the Influence of Simvastatin [MD thesis]. Edinburgh, Scotland: University of Edinburgh; 2005.
2018	Raina DB. Biomaterials as Carriers for Bone Active Molecules: An Approach to Create Off-the-Shelf Bone Substitutes [PhD thesis]. Lund, Sweden: Lund University; 2018.
2013	Antolić A. Mitochondrial Contributions to Bone Health, an Investigation Using Two Different Animal Models of Mitochondrial Capacity [PhD thesis]. Hamilton, ON: McMaster University; September 2013.
2009	Miller ES. The Role of E2f4 in Cell Cycle Exit and Bone Development [PhD thesis]. Cambridge, MA: Massachusetts Institute of Technology; June 2009.
2011	Garrison JG. The Relative Importance of Stress State, Microarchitecture, and Damage Burden in the Failure Behavior of Trabecular Bone [PhD thesis]. University of Notre Dame; April 2011.
2020	Simfia I. Estrogen Deficiency Alters the Mechanobiological Responses of Osteoblasts and Osteocytes [PhD thesis]. National University of Ireland Galway; April 2020.
2019	Maynard RD. Establishing the Functional Role of Cped1* in the Genetic Regulation of the Osteoblast* [PhD thesis]. University of Rochester; 2019.
2009	Litzenberger JB. The Role of Integrin Signaling in Bone Mechanotransduction [PhD thesis]. Stanford University; 2009.
2012	Uzer G. Role of Fluid Shear Modulation on Bone Cell Metabolism During High-Frequency Oscillatory Vibrations [PhD thesis]. Stony Brook, NY: Stony Brook University; December 2012.
2004	Doschak MR. Bisphosphonate Antiresorptive Drug Use in a Rabbit Model of Osteoarthritis [PhD thesis]. Calgary, AB: University of Calgary; April 2004.
2004	LaMothe JM. Functional Adaptation of Bone [PhD thesis]. Calgary, AB: University of Calgary; September 2004.
2020	Pei S. Osteocyte Mechanosensing: Interstitial Fluid Flow, Cellular Response, and Turnover of Pericellular Matrix [PhD thesis]. University of Delaware; 2020.
2019	Küsters NV. Auswirkungen des Alters und der Knochenmikroarchitektur auf die trabekuläre Knochenmineralisationsdichteverteilung: Eine rasterelektronenmikroskopische Studie an 152 humanen Beckenkammbiopsien [PhD thesis]. Hamburg, Germany: Universität Hamburg; 2019.
2022	Blank MA. Defining Mechanisms by Which EphrinB2 in Osteocytes Controls Bone Strength and Material Quality [PhD thesis]. University of Melbourne; September 2022.
2019	Mei X. Microfluidic Platform for Investigating Osteocyte Mechanoregulation of Breast Cancer Bone Metastasis [Master's thesis]. University of Toronto; 2019.
2019	Putnam NE. Innate Immunity and Bone Remodeling During Staphylococcus Aureus Osteomyelitis [PhD thesis]. Nashville, TN: Vanderbilt University; June 30, 2019.