Sclerostin
Ensembl | |||||||||
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| RefSeq (protein) | |||||||||
| Location (UCSC) | Chr 17: 43.75 – 43.76 Mb | Chr 11: 101.85 – 101.86 Mb | |||||||
| PubMed search | [3] | [4] | |||||||
| View/Edit Human | View/Edit Mouse |
| Sclerostin | |||||||||
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| Identifiers | |||||||||
| Symbol | Sclerostin | ||||||||
| Pfam | PF05463 | ||||||||
| InterPro | IPR008835 | ||||||||
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Sclerostin is a
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]
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
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]
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
An antibody for sclerostin is being developed because of the protein's specificity to bone.
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000167941 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000001494 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- PMID 11179006.
- PMID 24667598.
- ^ "Entrez Gene: SOST sclerosteosis".
- PMID 19166819.
- ^ doi:10.1138/20050189.
- PMID 14633986.
- ^ PMID 15778503.
- S2CID 28614850.
- S2CID 9235535.
- PMID 20952383.
- ^ PMID 21254230.
- ^ PMID 23470835.
- ^ PMID 23017659.
- PMID 16081646.
- PMID 18089564.
- PMID 26056029.
- PMID 21436889.
- PMID 20051625.
- PMID 20188226.
- ^ "Postmenopauzale Osteoporose".
- ^ PMID 11836356.
- PMID 4867898.
- PMID 11181578.
- ^ "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.
- S2CID 1012895.
- S2CID 206003762.
- S2CID 38080680.
- .
- S2CID 25584452.
- PMID 27641143.
- PMID 31031968.
- S2CID 551897.
- ^ "FDA approves romosozumab for osteoporosis". www.healio.com. April 9, 2019. Retrieved 2019-05-11.
- PMID 31847708.
- ^ Victoria Rees (13 December 2019). "EC approves treatment for severe osteoporosis postmenopausal women". European Pharmaceutical Review. Retrieved 27 February 2020.
Further reading
- Balemans W, Van Hul W (2007). "Human genetics of SOST". Journal of Musculoskeletal & Neuronal Interactions. 6 (4): 355–6. PMID 17185822.
- 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. PMID 11836356.
- Staehling-Hampton K, Proll S, Paeper BW, Zhao L, Charmley P, Brown A, et al. (June 2002). "A 52-kb deletion in the SOST-MEOX1 intergenic region on 17q12-q21 is associated with van Buchem disease in the Dutch population". American Journal of Medical Genetics. 110 (2): 144–52. PMID 12116252.
- Balemans W, Foernzler D, Parsons C, Ebeling M, Thompson A, Reid DM, et al. (October 2002). "Lack of association between the SOST gene and bone mineral density in perimenopausal women: analysis of five polymorphisms". Bone. 31 (4): 515–9. PMID 12398949.
- Clark HF, Gurney AL, Abaya E, Baker K, Baldwin D, Brush J, et al. (October 2003). "The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment". Genome Research. 13 (10): 2265–70. PMID 12975309.
- Sevetson B, Taylor S, Pan Y (April 2004). "Cbfa1/RUNX2 directs specific expression of the sclerosteosis gene (SOST)". The Journal of Biological Chemistry. 279 (14): 13849–58. PMID 14739291.
- van Bezooijen RL, Roelen BA, Visser A, van der Wee-Pals L, de Wilt E, Karperien M, et al. (March 2004). "Sclerostin is an osteocyte-expressed negative regulator of bone formation, but not a classical BMP antagonist". The Journal of Experimental Medicine. 199 (6): 805–14. PMID 15024046.
- Winkler DG, Yu C, Geoghegan JC, Ojala EW, Skonier JE, Shpektor D, et al. (August 2004). "Noggin and sclerostin bone morphogenetic protein antagonists form a mutually inhibitory complex". The Journal of Biological Chemistry. 279 (35): 36293–8. PMID 15199066.
- Zhang Z, Henzel WJ (October 2004). "Signal peptide prediction based on analysis of experimentally verified cleavage sites". Protein Science. 13 (10): 2819–24. PMID 15340161.
- Sutherland MK, Geoghegan JC, Yu C, Turcott E, Skonier JE, Winkler DG, Latham JA (October 2004). "Sclerostin promotes the apoptosis of human osteoblastic cells: a novel regulation of bone formation". Bone. 35 (4): 828–35. PMID 15454089.
- Uitterlinden AG, Arp PP, Paeper BW, Charmley P, Proll S, Rivadeneira F, et al. (December 2004). "Polymorphisms in the sclerosteosis/van Buchem disease gene (SOST) region are associated with bone-mineral density in elderly whites". American Journal of Human Genetics. 75 (6): 1032–45. PMID 15514891.
- Winkler DG, Sutherland MS, Ojala E, Turcott E, Geoghegan JC, Shpektor D, et al. (January 2005). "Sclerostin inhibition of Wnt-3a-induced C3H10T1/2 cell differentiation is indirect and mediated by bone morphogenetic proteins". The Journal of Biological Chemistry. 280 (4): 2498–502. PMID 15545262.
- Poole KE, van Bezooijen RL, Loveridge N, Hamersma H, Papapoulos SE, Löwik CW, Reeve J (November 2005). "Sclerostin is a delayed secreted product of osteocytes that inhibits bone formation". FASEB Journal. 19 (13): 1842–4. S2CID 17000496.
- Gardner JC, van Bezooijen RL, Mervis B, Hamdy NA, Löwik CW, Hamersma H, et al. (December 2005). "Bone mineral density in sclerosteosis; affected individuals and gene carriers". The Journal of Clinical Endocrinology and Metabolism. 90 (12): 6392–5. PMID 16189254.