Osteoprotegerin (OPG), also known as osteoclastogenesis inhibitory factor (OCIF), or tumor necrosis factor receptor superfamily member 11B (TNFRSF11B), is a protein that in humans is encoded by the TNFRSF11Bgene.[1] Osteoprotegerin is a cytokine receptor, and a member of the tumor necrosis factor (TNF) receptor superfamily.
Osteoprotegerin is a basic glycoprotein comprising 401 amino acid residues arranged into 7 structural domains. It is found as either a 60-kDa monomer or 120-kDa dimer linked by disulfide bonds.[2]
Function
Osteoprotegerin is a decoy receptor for the receptor activator of nuclear factor kappa B ligand (RANKL). By binding RANKL, OPG prevents RANK-mediated nuclear factor kappa B (NF-κB) activation which is a central and rapid acting transcription factor for immune-related genes, and a key regulator of inflammation, innate immunity, and cell survival and differentiation.[3]
Osteoprotegerin levels are influenced by voltage-dependent calcium channels Cav1.2.[4]
OPG can reduce the production of osteoclasts by inhibiting the differentiation of osteoclast precursors (osteoclasts are related to monocytes/macrophages and are derived from granulocyte/macrophage-forming colony units (CFU-GM)) into osteoclasts and also regulates the resorption of osteoclasts in vitro and in vivo. OPG binding to RANKL on osteoblast/stromal cells, blocks the RANKL-RANK interaction between osteoblast/stromal cells and osteoclast precursors. This has the effect of inhibiting the differentiation of the osteoclast precursor into a mature osteoclast.
Regulation and therapeutic applications
Osteoprotegerin production is stimulated in vivo by the female sex hormone estrogen,[5] as well as the osteoporosis drug, strontium ranelate. Denosumab is a pharmacologic agent that in essence acts like osteoprotegerin as a decoy receptor for osteoblastic RANKL.
Recombinant human osteoprotegerin specifically acts on bone, increasing bone mineral density and bone volume. Space shuttle flight STS-108 in 2001 tested the effects of osteoprotegerin on mice in microgravity, finding that it did prevent increase in resorption and maintained mineralization.[6][7] Osteoprotegerin has been used experimentally to decrease bone resorption in women with postmenopausal osteoporosis and in patients with lytic bone metastases.
It has been found that osteoprotegerin is expressed on mesenchymal stem cells, which mediates their suppressive effect on osteoclastogenesis.[11]
In recent years, it has been hypothesized that osteoprotegerin may be a link between bone and cardiovascular disease.[12][13] It has been particularly related to the increase in cardiovascular risk in patients suffering from diabetes [14][15]
References
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↑Schoppet M, Preissner KT, Hofbauer LC (April 2002). "RANK ligand and osteoprotegerin: paracrine regulators of bone metabolism and vascular function". Arteriosclerosis, Thrombosis, and Vascular Biology. 22 (4): 549–53. doi:10.1161/01.ATV.0000012303.37971.DA. PMID11950689.
↑Krakauer T (2008). "Nuclear factor-kappaB: fine-tuning a central integrator of diverse biologic stimuli". International Reviews of Immunology. 27 (5): 286–92. doi:10.1080/08830180802317957. PMID18853340.
↑Bergh JJ, Xu Y, Farach-Carson MC (January 2004). "Osteoprotegerin expression and secretion are regulated by calcium influx through the L-type voltage-sensitive calcium channel". Endocrinology. 145 (1): 426–36. doi:10.1210/en.2003-0319. PMID14525906.
↑Bateman TA, Countryman S (April 2002). "Osteoprotegerin and bone loss associated with spaceflight". Drug Discovery Today. 7 (8): 456–7. doi:10.1016/S1359-6446(02)02260-2. PMID11965392.
↑Venuraju SM, Yerramasu A, Corder R, Lahiri A (May 2010). "Osteoprotegerin as a predictor of coronary artery disease and cardiovascular mortality and morbidity". Journal of the American College of Cardiology. 55 (19): 2049–61. doi:10.1016/j.jacc.2010.03.013. PMID20447527.
↑Ramos YF, Bos SD, van der Breggen R, Kloppenburg M, Ye K, Lameijer EW, Nelissen RG, Slagboom PE, Meulenbelt I (September 2015). "A gain of function mutation in TNFRSF11B encoding osteoprotegerin causes osteoarthritis with chondrocalcinosis". Annals of the Rheumatic Diseases. 74 (9): 1756–62. doi:10.1136/annrheumdis-2013-205149. PMID24743232.
↑Takano T, Li YJ, Kukita A, Yamaza T, Ayukawa Y, Moriyama K, Uehara N, Nomiyama H, Koyano K, Kukita T (March 2014). "Mesenchymal stem cells markedly suppress inflammatory bone destruction in rats with adjuvant-induced arthritis". Laboratory Investigation; A Journal of Technical Methods and Pathology. 94 (3): 286–96. doi:10.1038/labinvest.2013.152. PMID24395111.
↑Blázquez-Medela AM, García-Ortiz L, Gómez-Marcos MA, Recio-Rodriguez JI, Sánchez-Rodríguez A, López-Novoa JM, Martínez-Salgado C (May 2012). "Osteoprotegerin is associated with cardiovascular risk in hypertension and/or diabetes". European Journal of Clinical Investigation. 42 (5): 548–56. doi:10.1111/j.1365-2362.2011.02619.x. PMID22050177.
↑Masser, RE; Lenhard, MJ (2014). "Osteoprotegerin is a Better Serum Biomarker of Coronary Artery Calcification Scores than Osteocalcin in Type 2 Diabetes". Endocr pract. 6.
↑Blázquez-Medela AM, García-Ortiz L, Gómez-Marcos MA, Recio-Rodriguez JI, Sánchez-Rodríguez A, López-Novoa JM, Martínez-Salgado C (May 2012). "Osteoprotegerin is associated with cardiovascular risk in hypertension and/or diabetes". European Journal of Clinical Investigation. 42 (5): 548–56. doi:10.1111/j.1365-2362.2011.02619.x. PMID22050177.
↑Blázquez-Medela AM, López-Novoa JM, Martínez-Salgado C (July 2011). "Osteoprotegerin and diabetes-associated pathologies". Current Molecular Medicine. 11 (5): 401–16. doi:10.2174/156652411795976565. PMID21568931.
Further reading
Blázquez-Medela AM, López-Novoa JM, Martínez-Salgado C (July 2011). "Osteoprotegerin and diabetes-associated pathologies". Current Molecular Medicine. 11 (5): 401–16. doi:10.2174/156652411795976565. PMID21568931.
Hofbauer LC, Neubauer A, Heufelder AE (August 2001). "Receptor activator of nuclear factor-kappaB ligand and osteoprotegerin: potential implications for the pathogenesis and treatment of malignant bone diseases". Cancer. 92 (3): 460–70. doi:10.1002/1097-0142(20010801)92:3<460::AID-CNCR1344>3.0.CO;2-D. PMID11505389.
Buckley KA, Fraser WD (November 2002). "Receptor activator for nuclear factor kappaB ligand and osteoprotegerin: regulators of bone physiology and immune responses/potential therapeutic agents and biochemical markers". Annals of Clinical Biochemistry. 39 (Pt 6): 551–6. doi:10.1258/000456302760413324. PMID12564836.
Kimberley FC, Screaton GR (October 2004). "Following a TRAIL: update on a ligand and its five receptors". Cell Research. 14 (5): 359–72. doi:10.1038/sj.cr.7290236. PMID15538968.
Collin-Osdoby P (November 2004). "Regulation of vascular calcification by osteoclast regulatory factors RANKL and osteoprotegerin". Circulation Research. 95 (11): 1046–57. doi:10.1161/01.RES.0000149165.99974.12. PMID15564564.
Whyte MP, Mumm S (September 2004). "Heritable disorders of the RANKL/OPG/RANK signaling pathway". Journal of Musculoskeletal & Neuronal Interactions. 4 (3): 254–67. PMID15615493.
Anandarajah AP, Schwarz EM (February 2006). "Anti-RANKL therapy for inflammatory bone disorders: Mechanisms and potential clinical applications". Journal of Cellular Biochemistry. 97 (2): 226–32. doi:10.1002/jcb.20674. PMID16240334.
Baud'huin M, Duplomb L, Ruiz Velasco C, Fortun Y, Heymann D, Padrines M (February 2007). "Key roles of the OPG-RANK-RANKL system in bone oncology". Expert Review of Anticancer Therapy. 7 (2): 221–32. doi:10.1586/14737140.7.2.221. PMID17288531.
Maruyama K, Sugano S (January 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID8125298.
Tsuda E, Goto M, Mochizuki S, Yano K, Kobayashi F, Morinaga T, Higashio K (May 1997). "Isolation of a novel cytokine from human fibroblasts that specifically inhibits osteoclastogenesis". Biochemical and Biophysical Research Communications. 234 (1): 137–42. doi:10.1006/bbrc.1997.6603. PMID9168977.
Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (October 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID9373149.
Tan KB, Harrop J, Reddy M, Young P, Terrett J, Emery J, Moore G, Truneh A (December 1997). "Characterization of a novel TNF-like ligand and recently described TNF ligand and TNF receptor superfamily genes and their constitutive and inducible expression in hematopoietic and non-hematopoietic cells". Gene. 204 (1–2): 35–46. doi:10.1016/S0378-1119(97)00509-X. PMID9434163.
Yamaguchi K, Kinosaki M, Goto M, Kobayashi F, Tsuda E, Morinaga T, Higashio K (February 1998). "Characterization of structural domains of human osteoclastogenesis inhibitory factor". The Journal of Biological Chemistry. 273 (9): 5117–23. doi:10.1074/jbc.273.9.5117. PMID9478964.
Yasuda H, Shima N, Nakagawa N, Mochizuki SI, Yano K, Fujise N, Sato Y, Goto M, Yamaguchi K, Kuriyama M, Kanno T, Murakami A, Tsuda E, Morinaga T, Higashio K (March 1998). "Identity of osteoclastogenesis inhibitory factor (OCIF) and osteoprotegerin (OPG): a mechanism by which OPG/OCIF inhibits osteoclastogenesis in vitro". Endocrinology. 139 (3): 1329–37. doi:10.1210/en.139.3.1329. PMID9492069.
Tomoyasu A, Goto M, Fujise N, Mochizuki S, Yasuda H, Morinaga T, Tsuda E, Higashio K (April 1998). "Characterization of monomeric and homodimeric forms of osteoclastogenesis inhibitory factor". Biochemical and Biophysical Research Communications. 245 (2): 382–7. doi:10.1006/bbrc.1998.8443. PMID9571159.
Emery JG, McDonnell P, Burke MB, Deen KC, Lyn S, Silverman C, Dul E, Appelbaum ER, Eichman C, DiPrinzio R, Dodds RA, James IE, Rosenberg M, Lee JC, Young PR (June 1998). "Osteoprotegerin is a receptor for the cytotoxic ligand TRAIL". The Journal of Biological Chemistry. 273 (23): 14363–7. doi:10.1074/jbc.273.23.14363. PMID9603945.
Morinaga T, Nakagawa N, Yasuda H, Tsuda E, Higashio K (June 1998). "Cloning and characterization of the gene encoding human osteoprotegerin/osteoclastogenesis-inhibitory factor". European Journal of Biochemistry / FEBS. 254 (3): 685–91. doi:10.1046/j.1432-1327.1998.2540685.x. PMID9688283.
Blázquez-Medela AM, López-Novoa JM, Martínez-Salgado C (July 2011). "Osteoprotegerin and diabetes-associated pathologies". Current Molecular Medicine. 11 (5): 401–16. doi:10.2174/156652411795976565. PMID21568931.