Sclerostin

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External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez
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Sclerostin
Identifiers
SymbolSclerostin
PfamPF05463
InterProIPR008835

Sclerostin is a protein that in humans is encoded by the SOST gene.[1][2]

Sclerostin is a secreted glycoprotein with a C-terminal cysteine knot-like (CTCK) domain and sequence similarity to the DAN (differential screening-selected gene aberrative in neuroblastoma) family of bone morphogenetic protein (BMP) antagonists. Sclerostin is produced primarily by the osteocyte but is also expressed in other tissues,[3] and has anti-anabolic effects on bone formation.[4]

Structure

The sclerostin protein, with a length of 213 residues, has a secondary structure that has been determined by protein NMR to be 28% beta sheet (6 strands; 32 residues).[5]

Function

Sclerostin, the product of the SOST gene, located on chromosome 17q12–q21 in humans,[6] was originally believed to be a non-classical bone morphogenetic protein (BMP) antagonist.[7] More recently, sclerostin has been identified as binding to LRP5/6 receptors and inhibiting the Wnt signaling pathway.[8][9] The inhibition of the Wnt pathway leads to decreased bone formation.[8] Although the underlying mechanisms are unclear, it is believed that the antagonism of BMP-induced bone formation by sclerostin is mediated by Wnt signaling, but not BMP signaling pathways.[10][11] Sclerostin is expressed in osteocytes and some chondrocytes and it inhibits bone formation by osteoblasts.[12][13][14]

Sclerostin production by osteocytes is inhibited by parathyroid hormone,[14][15] mechanical loading[16] and cytokines including prostaglandin E2,[17] oncostatin M, cardiotrophin-1 and leukemia inhibitory factor.[18] Sclerostin production is increased by calcitonin.[19] Thus, osteoblast activity is self regulated by a negative feedback system.[20]

Clinical significance

Mutations in the gene that encodes the sclerostin protein are associated with disorders associated with high bone mass, sclerosteosis and van Buchem disease.[6]

van Buchem disease is also an autosomal recessive skeletal disease characterized by bone overgrowth.[21] It was first described in 1955 as "hyperostosis corticalis generalisata familiaris", but was given the current name in 1968.[21][22] Excessive bone formation is most prominent in the skull, mandible, clavicle, ribs and diaphyses of long bones and bone formation occurs throughout life.[21] It is a very rare condition with about 30 known cases in 2002.[21] In 1967 van Buchem characterized the disease in 15 patients of Dutch origin.[21] Patients with sclerosteosis are distinguished from those with van Buchem disease because they are often taller and have hand malformations.[23] In the late 1990s, scientists at the company Chiroscience and the University of Cape Town determined that a "single mutation" in the gene was responsible for the disorder.[24]

An antibody for sclerostin is being developed because of the protein’s specificity to bone.[12] Its use has increased bone growth in preclinical trials in osteoporotic rats and monkeys.[25][26] In a Phase I study, a single dose of anti-sclerostin antibody from Amgen (Romosozumab) increased bone density in the hip and spine in healthy men and postmenopausal women and the drug was well tolerated.[27] In a Phase II trial, one year of the antibody treatment in osteoporotic women increased bone density more than bisphosphonate and teriparatide treatment; it had mild injection side effects.[13][28] A Phase II trial of a monoclonal human antibody to sclerostin from Eli Lilly had positive effects on post-menopausal women. Monthly treatments of the antibody for one year increased the bone mineral density of the spine and hip by 18 percent and 6 percent, respectively, compared to the placebo group.[29] In a Phase III trial, one year of Romosozumab treatment in post-menopausal women reduced the risk of vertebral fractures compared to the placebo group. It also increased the bone mineral density in the lumbar spine (13.3% versus 0.0%), femoral neck (5.2% versus -0.7%) and total hip (6.8% versus 0.0%) compared to the placebo group. Adverse events were balanced between the groups.[30]

References

  1. Brunkow ME, Gardner JC, Van Ness J, Paeper BW, Kovacevich BR, Proll S, Skonier JE, Zhao L, Sabo PJ, Fu Y, Alisch RS, Gillett L, Colbert T, Tacconi P, Galas D, Hamersma H, Beighton P, Mulligan J (Mar 2001). "Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein". American Journal of Human Genetics. 68 (3): 577–89. doi:10.1086/318811. PMC 1274471. PMID 11179006.
  2. Balemans W, Ebeling M, Patel N, Van Hul E, Olson P, Dioszegi M, Lacza C, Wuyts W, Van Den Ende J, Willems P, Paes-Alves AF, Hill S, Bueno M, Ramos FJ, Tacconi P, Dikkers FG, Stratakis C, Lindpaintner K, Vickery B, Foernzler D, Van Hul W (Mar 2001). "Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST)". Human Molecular Genetics. 10 (5): 537–43. doi:10.1093/hmg/10.5.537. PMID 11181578.
  3. Hernandez, Paula; Whitty, Ciara; John Wardale, R.; Henson, Frances M.D. (2014). "New insights into the location and form of sclerostin". Biochemical and Biophysical Research Communications. 446 (4): 1108–1113. doi:10.1016/j.bbrc.2014.03.079. PMID 24667598.
  4. "Entrez Gene: SOST sclerosteosis".
  5. Weidauer SE, Schmieder P, Beerbaum M, Schmitz W, Oschkinat H, Mueller TD (Feb 2009). "NMR structure of the Wnt modulator protein Sclerostin". Biochem Biophys Res Commun. 380 (1): 160–5. doi:10.1016/j.bbrc.2009.01.062. PMID 19166819.
  6. 6.0 6.1 Van Bezooijen, R. L.; Papapoulos, S. E.; Hamdy, N. A.; Ten Dijke, P.; Löwik, C. W. (2005). "Control of bone formation by osteocytes? Lessons from the rare skeletal disorders sclerosteosis and van Buchem disease". BoneKEy-Osteovision. 2 (12): 33–38. doi:10.1138/20050189.
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  9. Ellies DL, Viviano B, McCarthy J, Rey JP, Itasaki N, Saunders S, Krumlauf R (Nov 2006). "Bone density ligand, Sclerostin, directly interacts with LRP5 but not LRP5G171V to modulate Wnt activity". Journal of Bone and Mineral Research. 21 (11): 1738–49. doi:10.1359/jbmr.060810. PMID 17002572.
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  11. Krause C, Korchynskyi O, de Rooij K, Weidauer SE, de Gorter DJ, van Bezooijen RL, Hatsell S, Economides AN, Mueller TD, Löwik CW, ten Dijke P (Dec 2010). "Distinct modes of inhibition by sclerostin on bone morphogenetic protein and Wnt signaling pathways". The Journal of Biological Chemistry. 285 (53): 41614–26. doi:10.1074/jbc.M110.153890. PMC 3009889. PMID 20952383.
  12. 12.0 12.1 Bonewald LF (Feb 2011). "The amazing osteocyte". Journal of Bone and Mineral Research. 26 (2): 229–38. doi:10.1002/jbmr.320. PMC 3179345. PMID 21254230.
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  15. Bellido T, Ali AA, Gubrij I, Plotkin LI, Fu Q, O'Brien CA, Manolagas SC, Jilka RL (Nov 2005). "Chronic elevation of parathyroid hormone in mice reduces expression of sclerostin by osteocytes: a novel mechanism for hormonal control of osteoblastogenesis". Endocrinology. 146 (11): 4577–83. doi:10.1210/en.2005-0239. PMID 16081646.
  16. Robling AG, Niziolek PJ, Baldridge LA, Condon KW, Allen MR, Alam I, Mantila SM, Gluhak-Heinrich J, Bellido TM, Harris SE, Turner CH (Feb 2008). "Mechanical stimulation of bone in vivo reduces osteocyte expression of Sost/sclerostin". The Journal of Biological Chemistry. 283 (9): 5866–75. doi:10.1074/jbc.M705092200. PMID 18089564.
  17. Genetos DC, Yellowley CE, Loots GG (March 2011). "Prostaglandin E2 signals through PTGER2 to regulate sclerostin expression". PLOS ONE. 6 (3): e17772. doi:10.1371/journal.pone.0017772. PMC 3059227. PMID 21436889.
  18. Walker EC, McGregor NE, Poulton IJ, Solano M, Pompolo S, Fernandes TJ, Constable MJ, Nicholson GC, Zhang JG, Nicola NA, Gillespie MT, Martin TJ, Sims NA (Feb 2010). "Oncostatin M promotes bone formation independently of resorption when signaling through leukemia inhibitory factor receptor in mice". The Journal of Clinical Investigation. 120 (2): 582–92. doi:10.1172/JCI40568. PMC 2810087. PMID 20051625.
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  20. http://users.telenet.be/zeldzame.ziekten/List.o/Pmenoposteo.htm
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  22. Fosmoe RJ, Holm RS, Hildreth RC (Apr 1968). "Van Buchem's disease (hyperostosis corticalis generalisata familiaris). A case report". Radiology. 90 (4): 771–4. doi:10.1148/90.4.771. PMID 4867898.
  23. Balemans W, Ebeling M, Patel N, Van Hul E, Olson P, Dioszegi M, Lacza C, Wuyts W, Van Den Ende J, Willems P, Paes-Alves AF, Hill S, Bueno M, Ramos FJ, Tacconi P, Dikkers FG, Stratakis C, Lindpaintner K, Vickery B, Foernzler D, Van Hul W (Mar 2001). "Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST)". Human Molecular Genetics. 10 (5): 537–43. doi:10.1093/hmg/10.5.537. PMID 11181578.
  24. "Scientists fine 'bone mass gene' in South Africans suffering from inherited disease". Oshkosh Northwestern. Oshkosh, Wisconsin. Associated Press. 26 May 1999. p. B5. Retrieved 24 December 2018 – via Newspapers.com.
  25. Li X, Ominsky MS, Warmington KS, Morony S, Gong J, Cao J, Gao Y, Shalhoub V, Tipton B, Haldankar R, Chen Q, Winters A, Boone T, Geng Z, Niu QT, Ke HZ, Kostenuik PJ, Simonet WS, Lacey DL, Paszty C (Apr 2009). "Sclerostin antibody treatment increases bone formation, bone mass, and bone strength in a rat model of postmenopausal osteoporosis". Journal of Bone and Mineral Research. 24 (4): 578–88. doi:10.1359/jbmr.081206. PMID 19049336.
  26. Ominsky MS, Vlasseros F, Jolette J, Smith SY, Stouch B, Doellgast G, Gong J, Gao Y, Cao J, Graham K, Tipton B, Cai J, Deshpande R, Zhou L, Hale MD, Lightwood DJ, Henry AJ, Popplewell AG, Moore AR, Robinson MK, Lacey DL, Simonet WS, Paszty C (May 2010). "Two doses of sclerostin antibody in cynomolgus monkeys increases bone formation, bone mineral density, and bone strength". Journal of Bone and Mineral Research. 25 (5): 948–59. doi:10.1002/jbmr.14. PMID 20200929.
  27. Padhi D, Jang G, Stouch B, Fang L, Posvar E (Jan 2011). "Single-dose, placebo-controlled, randomized study of AMG 785, a sclerostin monoclonal antibody". Journal of Bone and Mineral Research. 26 (1): 19–26. doi:10.1002/jbmr.173. PMID 20593411.
  28. Reid, I. R. (2012). "Osteoporosis treatment at ASBMR 2012". IBMS BoneKEy. 9. doi:10.1038/bonekey.2012.245.
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  30. Cosman, et al. (2016). "Romosozumab Treatment in Postmenopausal Women with Osteoporosis". The New England Journal of Medicine. 375 (16): 1532–1543. doi:10.1056/NEJMoa1607948. PMID 27641143.

Further reading

External links