Sclerostin

Sclerostin is a protein that in humans is encoded by the SOST gene.[5] It 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,[6] and has anti-anabolic effects on bone formation.[7]

"SOST" redirects here. For other uses, see Sost (disambiguation).
SOST
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesSOST, CDD, SOST1, VBCH, DAND6, sclerostin, Sclerostin
External IDsOMIM: 605740 MGI: 1921749 HomoloGene: 11542 GeneCards: SOST
Orthologs
SpeciesHumanMouse
Entrez

50964

74499

Ensembl

ENSG00000167941

ENSMUSG00000001494

UniProt

Q9BQB4

Q99P68

RefSeq (mRNA)

NM_025237

NM_024449

RefSeq (protein)

NP_079513

NP_077769

Location (UCSC)Chr 17: 43.75 – 43.76 MbChr 11: 101.85 – 101.86 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse
Sclerostin
Identifiers
SymbolSclerostin
PfamPF05463
InterProIPR008835
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary

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).[8]

Function

Sclerostin, the product of the SOST gene, located on chromosome 17q12–q21 in humans,[9] was originally believed to be a non-classical bone morphogenetic protein (BMP) antagonist.[10] More recently, sclerostin has been identified as binding to LRP5/6 receptors and inhibiting the Wnt signaling pathway.[11][12] The inhibition of the Wnt pathway leads to decreased bone formation.[11] 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.[13][14] Sclerostin is expressed in osteocytes and some chondrocytes and it inhibits bone formation by osteoblasts.[15][16][17]

Sclerostin production by osteocytes is inhibited by parathyroid hormone,[17][18] mechanical loading,[19] estrogen[20] and cytokines including prostaglandin E2,[21] oncostatin M, cardiotrophin-1 and leukemia inhibitory factor.[22] Sclerostin production is increased by calcitonin.[23] Thus, osteoblast activity is self regulated by a negative feedback system.[24]

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.[9]

van Buchem disease is an autosomal recessive skeletal disease characterized by bone overgrowth.[25] It was first described in 1955 as "hyperostosis corticalis generalisata familiaris", but was given the current name in 1968.[25][26] Excessive bone formation is most prominent in the skull, mandible, clavicle, ribs and diaphyses of long bones and bone formation occurs throughout life.[25] It is a very rare condition with about 30 known cases in 2002.[25] In 1967 van Buchem characterized the disease in 15 patients of Dutch origin.[25] Patients with sclerosteosis are distinguished from those with van Buchem disease because they are often taller and have hand malformations.[27] 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.[28]

Sclerostin antibody
Main article: Romosozumab

An antibody for sclerostin is being developed because of the protein's specificity to bone.[15] Its use has increased bone growth in preclinical trials in osteoporotic rats and monkeys.[29][30] 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.[31] 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.[16][32] 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.[33] 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.[34] Sclerostin has significance within the field of dentistry[35] and regenerative strategies which target sclerostin are in development.[36] In April 2019, the Food and Drug Administration approved Romosozumab for use in women with a very high risk of osteoporotic fracture.[37] It was also approved for use in Japan[38] and the European Union in 2019.[39]

References
  1. GRCh38: Ensembl release 89: ENSG00000167941 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000001494 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. Brunkow ME, Gardner JC, Van Ness J, Paeper BW, Kovacevich BR, Proll S, et al. (March 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.
  6. Hernandez P, Whitty C, John Wardale R, Henson FM (April 2014). "New insights into the location and form of sclerostin". Biochemical and Biophysical Research Communications. 446 (4): 1108–13. doi:10.1016/j.bbrc.2014.03.079. PMID 24667598.
  7. "Entrez Gene: SOST sclerosteosis".
  8. Weidauer SE, Schmieder P, Beerbaum M, Schmitz W, Oschkinat H, Mueller TD (February 2009). "NMR structure of the Wnt modulator protein Sclerostin". Biochemical and Biophysical Research Communications. 380 (1): 160–5. doi:10.1016/j.bbrc.2009.01.062. PMID 19166819.
  9. 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.
  10. Winkler DG, Sutherland MK, Geoghegan JC, Yu C, Hayes T, Skonier JE, et al. (December 2003). "Osteocyte control of bone formation via sclerostin, a novel BMP antagonist". The EMBO Journal. 22 (23): 6267–76. doi:10.1093/emboj/cdg599. PMC 291840. PMID 14633986.
  11. Li X, Zhang Y, Kang H, Liu W, Liu P, Zhang J, et al. (May 2005). "Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling". The Journal of Biological Chemistry. 280 (20): 19883–7. doi:10.1074/jbc.M413274200. PMID 15778503.
  12. Ellies DL, Viviano B, McCarthy J, Rey JP, Itasaki N, Saunders S, Krumlauf R (November 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. S2CID 28614850.
  13. van Bezooijen RL, Svensson JP, Eefting D, Visser A, van der Horst G, Karperien M, et al. (January 2007). "Wnt but not BMP signaling is involved in the inhibitory action of sclerostin on BMP-stimulated bone formation". Journal of Bone and Mineral Research. 22 (1): 19–28. doi:10.1359/jbmr.061002. PMID 17032150. S2CID 9235535.
  14. Krause C, Korchynskyi O, de Rooij K, Weidauer SE, de Gorter DJ, van Bezooijen RL, et al. (December 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.
  15. Bonewald LF (February 2011). "The amazing osteocyte". Journal of Bone and Mineral Research. 26 (2): 229–38. doi:10.1002/jbmr.320. PMC 3179345. PMID 21254230.
  16. Burgers TA, Williams BO (June 2013). "Regulation of Wnt/β-catenin signaling within and from osteocytes". Bone. 54 (2): 244–9. doi:10.1016/j.bone.2013.02.022. PMC 3652284. PMID 23470835.
  17. Bellido T, Saini V, Pajevic PD (June 2013). "Effects of PTH on osteocyte function". Bone. 54 (2): 250–7. doi:10.1016/j.bone.2012.09.016. PMC 3552098. PMID 23017659.
  18. Bellido T, Ali AA, Gubrij I, Plotkin LI, Fu Q, O'Brien CA, et al. (November 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.
  19. Robling AG, Niziolek PJ, Baldridge LA, Condon KW, Allen MR, Alam I, et al. (February 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.
  20. Appelman-Dijkstra, Natasha M.; Papapoulos, Socrates E. (2015). "Modulating Bone Resorption and Bone Formation in Opposite Directions in the Treatment of Postmenopausal Osteoporosis". Drugs. 75 (10): 1049–1058. doi:10.1007/s40265-015-0417-7. PMC 4498277. PMID 26056029.
  21. Genetos DC, Yellowley CE, Loots GG (March 2011). "Prostaglandin E2 signals through PTGER2 to regulate sclerostin expression". PLOS ONE. 6 (3): e17772. Bibcode:2011PLoSO...617772G. doi:10.1371/journal.pone.0017772. PMC 3059227. PMID 21436889.
  22. Walker EC, McGregor NE, Poulton IJ, Solano M, Pompolo S, Fernandes TJ, et al. (February 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.
  23. Gooi JH, Pompolo S, Karsdal MA, Kulkarni NH, Kalajzic I, McAhren SH, et al. (June 2010). "Calcitonin impairs the anabolic effect of PTH in young rats and stimulates expression of sclerostin by osteocytes" (PDF). Bone. 46 (6): 1486–97. doi:10.1016/j.bone.2010.02.018. hdl:11343/52365. PMID 20188226.
  24. "Postmenopauzale Osteoporose".
  25. Balemans W, Patel N, Ebeling M, Van Hul E, Wuyts W, Lacza C, et al. (February 2002). "Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease". Journal of Medical Genetics. 39 (2): 91–7. doi:10.1136/jmg.39.2.91. PMC 1735035. PMID 11836356.
  26. Fosmoe RJ, Holm RS, Hildreth RC (April 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.
  27. Balemans W, Ebeling M, Patel N, Van Hul E, Olson P, Dioszegi M, et al. (March 2001). "Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST)" (PDF). Human Molecular Genetics. 10 (5): 537–43. doi:10.1093/hmg/10.5.537. PMID 11181578.
  28. "Scientists find '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.
  29. Li X, Ominsky MS, Warmington KS, Morony S, Gong J, Cao J, et al. (April 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. S2CID 1012895.
  30. Ominsky MS, Vlasseros F, Jolette J, Smith SY, Stouch B, Doellgast G, et al. (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. S2CID 206003762.
  31. Padhi D, Jang G, Stouch B, Fang L, Posvar E (January 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. S2CID 38080680.
  32. Reid, I. R. (2012). "Osteoporosis treatment at ASBMR 2012". IBMS BoneKEy. 9. doi:10.1038/bonekey.2012.245.
  33. Recker RR, Benson CT, Matsumoto T, Bolognese MA, Robins DA, Alam J, et al. (February 2015). "A randomized, double-blind phase 2 clinical trial of blosozumab, a sclerostin antibody, in postmenopausal women with low bone mineral density". Journal of Bone and Mineral Research. 30 (2): 216–24. doi:10.1002/jbmr.2351. PMID 25196993. S2CID 25584452.
  34. Cosman F, Crittenden DB, Adachi JD, Binkley N, Czerwinski E, Ferrari S, et al. (October 2016). "Romosozumab Treatment in Postmenopausal Women with Osteoporosis". The New England Journal of Medicine. 375 (16): 1532–1543. doi:10.1056/NEJMoa1607948. PMID 27641143.
  35. Samiei M, Janjić K, Cvikl B, Moritz A, Agis H (January 2019). "The role of sclerostin and dickkopf-1 in oral tissues - A review from the perspective of the dental disciplines". F1000Research. 8: 128. doi:10.12688/f1000research.17801.1. PMC 6468704. PMID 31031968.
  36. Taut AD, Jin Q, Chung JH, Galindo-Moreno P, Yi ES, Sugai JV, et al. (November 2013). "Sclerostin antibody stimulates bone regeneration after experimental periodontitis" (PDF). Journal of Bone and Mineral Research. 28 (11): 2347–56. doi:10.1002/jbmr.1984. PMID 23712325. S2CID 551897.
  37. "FDA approves romosozumab for osteoporosis". www.healio.com. April 9, 2019. Retrieved 2019-05-11.
  38. Kaplon H, Muralidharan M, Schneider Z, Reichert JM (2020). "Antibodies to watch in 2020". mAbs. 12 (1): 1703531. doi:10.1080/19420862.2019.1703531. PMC 6973335. PMID 31847708.
  39. Victoria Rees (13 December 2019). "EC approves treatment for severe osteoporosis postmenopausal women". European Pharmaceutical Review. Retrieved 27 February 2020.

Further reading
This article is issued from Wikipedia. The text is licensed under Creative Commons - Attribution - Sharealike. Additional terms may apply for the media files.