Biology:Sclerostin

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example
Sclerostin
Identifiers
SymbolSclerostin
PfamPF05463
InterProIPR008835

Sclerostin is a protein that in humans is encoded by the SOST gene.[1] 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,[2] and has anti-anabolic effects on bone formation.[3]

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).[4]

Function

Sclerostin, the product of the SOST gene, located on chromosome 17q12–q21 in humans,[5] was originally believed to be a non-classical bone morphogenetic protein (BMP) antagonist.[6] More recently, sclerostin has been identified as binding to LRP5/6 receptors and inhibiting the Wnt signaling pathway.[7][8] The inhibition of the Wnt pathway leads to decreased bone formation.[7] 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.[9][10] Sclerostin is expressed in osteocytes and some chondrocytes and it inhibits bone formation by osteoblasts.[11][12][13]

Sclerostin production by osteocytes is inhibited by parathyroid hormone,[13][14] mechanical loading,[15] estrogen[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.[5]

van Buchem disease is 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]

Sclerostin antibody

Main page: Chemistry:Romosozumab

An antibody for sclerostin is being developed because of the protein's specificity to bone.[11] 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.[12][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] Sclerostin has significance within the field of dentistry[31] and regenerative strategies which target sclerostin are in development.[32] In April 2019, the Food and Drug Administration approved Romosozumab for use in women with a very high risk of osteoporotic fracture.[33] It was also approved for use in Japan[34] and the European Union in 2019.[35]

References

  1. ↑ "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. March 2001. doi:10.1086/318811. PMID 11179006. 
  2. ↑ "New insights into the location and form of sclerostin". Biochemical and Biophysical Research Communications 446 (4): 1108–13. April 2014. doi:10.1016/j.bbrc.2014.03.079. PMID 24667598. 
  3. ↑ "Entrez Gene: SOST sclerosteosis". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=50964. 
  4. ↑ "NMR structure of the Wnt modulator protein Sclerostin". Biochemical and Biophysical Research Communications 380 (1): 160–5. February 2009. doi:10.1016/j.bbrc.2009.01.062. PMID 19166819. 
  5. ↑ 5.0 5.1 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. 
  6. ↑ "Osteocyte control of bone formation via sclerostin, a novel BMP antagonist". The EMBO Journal 22 (23): 6267–76. December 2003. doi:10.1093/emboj/cdg599. PMID 14633986. 
  7. ↑ 7.0 7.1 "Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling". The Journal of Biological Chemistry 280 (20): 19883–7. May 2005. doi:10.1074/jbc.M413274200. PMID 15778503. 
  8. ↑ "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. November 2006. doi:10.1359/jbmr.060810. PMID 17002572. 
  9. ↑ "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. January 2007. doi:10.1359/jbmr.061002. PMID 17032150. 
  10. ↑ "Distinct modes of inhibition by sclerostin on bone morphogenetic protein and Wnt signaling pathways". The Journal of Biological Chemistry 285 (53): 41614–26. December 2010. doi:10.1074/jbc.M110.153890. PMID 20952383. 
  11. ↑ 11.0 11.1 "The amazing osteocyte". Journal of Bone and Mineral Research 26 (2): 229–38. February 2011. doi:10.1002/jbmr.320. PMID 21254230. 
  12. ↑ 12.0 12.1 "Regulation of Wnt/β-catenin signaling within and from osteocytes". Bone 54 (2): 244–9. June 2013. doi:10.1016/j.bone.2013.02.022. PMID 23470835. 
  13. ↑ 13.0 13.1 "Effects of PTH on osteocyte function". Bone 54 (2): 250–7. June 2013. doi:10.1016/j.bone.2012.09.016. PMID 23017659. 
  14. ↑ "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. November 2005. doi:10.1210/en.2005-0239. PMID 16081646. 
  15. ↑ "Mechanical stimulation of bone in vivo reduces osteocyte expression of Sost/sclerostin". The Journal of Biological Chemistry 283 (9): 5866–75. February 2008. doi:10.1074/jbc.M705092200. PMID 18089564. 
  16. ↑ 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. PMID 26056029. 
  17. ↑ "Prostaglandin E2 signals through PTGER2 to regulate sclerostin expression". PLOS ONE 6 (3): e17772. March 2011. doi:10.1371/journal.pone.0017772. PMID 21436889. Bibcode: 2011PLoSO...617772G. 
  18. ↑ "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. February 2010. doi:10.1172/JCI40568. PMID 20051625. 
  19. ↑ "Calcitonin impairs the anabolic effect of PTH in young rats and stimulates expression of sclerostin by osteocytes". Bone 46 (6): 1486–97. June 2010. doi:10.1016/j.bone.2010.02.018. PMID 20188226. http://minerva-access.unimelb.edu.au/bitstream/11343/52365/5/Calcitonin%20impairs%20the%20anabolic%20effect%20of%20PTH%20in%20young%20rats%20-%20Gooi%20et%20al.pdf. 
  20. ↑ "Postmenopauzale Osteoporose". http://users.telenet.be/zeldzame.ziekten/List.o/Pmenoposteo.htm. 
  21. ↑ 21.0 21.1 21.2 21.3 21.4 "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. February 2002. doi:10.1136/jmg.39.2.91. PMID 11836356. 
  22. ↑ "Van Buchem's disease (hyperostosis corticalis generalisata familiaris). A case report". Radiology 90 (4): 771–4. April 1968. doi:10.1148/90.4.771. PMID 4867898. 
  23. ↑ "Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST)". Human Molecular Genetics 10 (5): 537–43. March 2001. doi:10.1093/hmg/10.5.537. PMID 11181578. http://repositorio.ufba.br/ri/bitstream/ri/7762/1/Balemans.pdf. 
  24. ↑ "Scientists find 'bone mass gene' in South Africans suffering from inherited disease". Oshkosh Northwestern. Associated Press (Oshkosh, Wisconsin): p. B5. 26 May 1999. https://www.newspapers.com/clip/26480491/bone_mass_gene/. 
  25. ↑ "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. April 2009. doi:10.1359/jbmr.081206. PMID 19049336. 
  26. ↑ "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. May 2010. doi:10.1002/jbmr.14. PMID 20200929. 
  27. ↑ "Single-dose, placebo-controlled, randomized study of AMG 785, a sclerostin monoclonal antibody". Journal of Bone and Mineral Research 26 (1): 19–26. January 2011. 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. 
  29. ↑ "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. February 2015. doi:10.1002/jbmr.2351. PMID 25196993. 
  30. ↑ "Romosozumab Treatment in Postmenopausal Women with Osteoporosis". The New England Journal of Medicine 375 (16): 1532–1543. October 2016. doi:10.1056/NEJMoa1607948. PMID 27641143. https://archive-ouverte.unige.ch/unige:89797. 
  31. ↑ "The role of sclerostin and dickkopf-1 in oral tissues - A review from the perspective of the dental disciplines". F1000Research 8: 128. January 2019. doi:10.12688/f1000research.17801.1. PMID 31031968. 
  32. ↑ "Sclerostin antibody stimulates bone regeneration after experimental periodontitis". Journal of Bone and Mineral Research 28 (11): 2347–56. November 2013. doi:10.1002/jbmr.1984. PMID 23712325. https://deepblue.lib.umich.edu/bitstream/2027.42/100280/1/jbmr1984.pdf. 
  33. ↑ "FDA approves romosozumab for osteoporosis" (in en). April 9, 2019. https://www.healio.com/endocrinology/bone-mineral-metabolism/news/online/%7B46cf9eb4-b0ed-4b7d-a4a2-f8eba9b0301b%7D/fda-approves-romosozumab-for-osteoporosis. 
  34. ↑ "Antibodies to watch in 2020". mAbs 12 (1): 1703531. 2020. doi:10.1080/19420862.2019.1703531. PMID 31847708. 
  35. ↑ Victoria Rees (13 December 2019). "EC approves treatment for severe osteoporosis postmenopausal women". European Pharmaceutical Review. https://www.europeanpharmaceuticalreview.com/news/107970/ec-approves-treatment-for-severe-osteoporosis-postmenopausal-women/. 

Further reading

External links



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