Osteoprotegerin

Tumor necrosis factor receptor superfamily, member 11b
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols TNFRSF11B ; OCIF; OPG; TR1
External IDs OMIM: 602643 MGI: 109587 HomoloGene: 1912 GeneCards: TNFRSF11B Gene
RNA expression pattern
More reference expression data
Orthologs
Species Human Mouse
Entrez 4982 18383
Ensembl ENSG00000164761 ENSMUSG00000063727
UniProt O00300 O08712
RefSeq (mRNA) NM_002546 NM_008764
RefSeq (protein) NP_002537 NP_032790
Location (UCSC) Chr 8:
118.92 – 118.95 Mb		 Chr 15:
54.25 – 54.28 Mb
PubMed search
Not to be confused with Osteopontin (OPN).

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 TNFRSF11B gene.[1] Osteoprotegerin is a cytokine receptor, and a member of the tumor necrosis factor (TNF) receptor superfamily.

Structure

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 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.

Clinical significance

Elevated OPG levels has been reported in heart diseases,[8] in placebo effect serum responses in IBS patients (doi:10.1111/j.1365-2982.2009.01440.x PMID 20028464) and in severe mental disorders.[9]

Mutations in TNFRSF11B are associated with osteoarthritis.[10]

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

  1. ↑ Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS, Lüthy R, Nguyen HQ, Wooden S, Bennett L, Boone T, Shimamoto G, DeRose M, Elliott R, Colombero A, Tan HL, Trail G, Sullivan J, Davy E, Bucay N, Renshaw-Gegg L, Hughes TM, Hill D, Pattison W, Campbell P, Sander S, Van G, Tarpley J, Derby P, Lee R, Boyle WJ (April 1997). "Osteoprotegerin: a novel secreted protein involved in the regulation of bone density". Cell 89 (2): 309–19. doi:10.1016/S0092-8674(00)80209-3. PMID 9108485.
  2. ↑ Schoppet M, Preissner KT, Hofbauer LC (April 2002). "RANK ligand and osteoprotegerin: paracrine regulators of bone metabolism and vascular function". Arterioscler. Thromb. Vasc. Biol. 22 (4): 549–53. doi:10.1161/01.ATV.0000012303.37971.DA. PMID 11950689.
  3. ↑ Krakauer T (2008). "Nuclear factor-kappaB: fine-tuning a central integrator of diverse biologic stimuli". Int. Rev. Immunol. 27 (5): 286–92. doi:10.1080/08830180802317957. PMID 18853340.
  4. ↑ PMID14525906
  5. ↑ Khosla S (December 2001). "Minireview: the OPG/RANKL/RANK system". Endocrinology 142 (12): 5050–5. doi:10.1210/en.142.12.5050. PMID 11713196.
  6. ↑ "Commercial Biomedical Testing Module: Effects of Osteoprotegerin on Bone Maintenance in Microgravity (CBTM)". U.S. National Aeronautics and Space Administration (NASA).
  7. ↑ Bateman TA, Countryman S (April 2002). "Osteoprotegerin and bone loss associated with spaceflight". Drug Discov. Today 7 (8): 456–7. doi:10.1016/S1359-6446(02)02260-2. PMID 11965392.
  8. ↑ Venuraju SM, Yerramasu A, Corder R, Lahiri A (May 2010). "Osteoprotegerin as a predictor of coronary artery disease and cardiovascular mortality and morbidity". J. Am. Coll. Cardiol. 55 (19): 2049–61. doi:10.1016/j.jacc.2010.03.013. PMID 20447527.
  9. ↑ Hope S, Melle I, Aukrust P, Agartz I, Lorentzen S, Steen NE, Djurovic S, Ueland T, Andreassen OA (September 2010). "Osteoprotegerin levels in patients with severe mental disorders". J Psychiatry Neurosci 35 (5): 304–10. doi:10.1503/jpn.090088. PMC 2928283. PMID 20569643.
  10. ↑ Ramos, Y. F (April 2014). "A gain of function mutation in TNFRSF11B encoding osteoprotegerin causes osteoarthritis with chondrocalcinosis..". Annals of the Rheumatic Diseases. doi:10.1136/annrheumdis-2013-205149. PMID 24743232.
  11. ↑ Takano T (Mar 2014). "Mesenchymal stem cells markedly suppress inflammatory bone destruction in rats with adjuvant-induced arthritis..". Lab Invest. 94 (3): 288–298. doi:10.1038/labinvest.2013.152. PMID 24395111.
  12. ↑ Blázquez-Medela, Ana M (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. PMID 22050177.
  13. ↑ 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.
  14. ↑ Blazquez-Medela, Ana M; García-Ortiz, Luis; Gómez-Marcos, Manuel A; Recio-Rodríguez, José I; López-Novoa, José M; 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. PMID 22050177. Retrieved 2014.
  15. ↑ Blázquez-Medela, Ana M; López-Novoa, José M; Martínez-Salgado, C (2011). "Osteoprotegerin and diabetes-associated pathologies". Current Molecular Medicine 11 (5): 401–16. doi:10.2174/156652411795976565. PMID 21568931. Retrieved 2014.

Further reading

External links

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