Sclerostin
Sclerostin is a protein that in humans is encoded by the SOST gene.[2][3]
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 by the osteocyte and has anti-anabolic effects on bone formation.[4]
Structure
The sclerostin protein, with a length of 213 residues, has a dssp secondary structure that is 28% beta sheet (6 strands; 32 residues).[1]
Function
Sclerostin, the product of the SOST gene, located on chromosome 17, locus q11.2 in humans, was originally believed to be a non-classical Bone morphogenetic protein (BMP) antagonist. More recently Sclerostin has been identified as binding to LRP5/6 receptors and inhibiting the Wnt signalling pathway .[5] Wnt pathway inhibition under these circumstances is antagonistic to bone formation (meaning Sclerostin antagonizes bone formation).[6] Although the underlying mechanisms are unclear, it is believed that the antagonism of BMP-induced bone formation by sclerostin is mediated by Wnt signalling, but not BMP signalling pathways.[7][8]The mechanism of action is likely to be similar for the related protein DKK1, which has a broader tissue distribution.
Sclerostin production by osteocytes is inhibited by parathyroid hormone, mechanical loading and cytokines including oncostatin M, cardiotrophin-1 and leukemia inhibitory factor. Sclerostin production is increased by calcitonin. Thus, osteoblast activity is self regulated by a negative feedback system.[9]
Clinical significance
Mutations of Sclerostin is associated with the syndrome Sclerosteosis in which there is an abnormal increase in the growth of bones due to lack of normal Sclerostin expression by osteocytes and a different set of mutations in the non-coding region of sclerostin are associated with Van Buchem's syndrome, a similar high bone mass phenotype. Sclerostin acts upon osteoblasts in the bone in a paracrine manner of unknown mechanism.
Currently an anti-sclerostin antibody for the treatment of osteoporosis is being co-developed by Amgen and UCB.[10] In addition, OsteoGeneX is developing small molecule inhibitors of sclerostin.[11]
References
- ^ a b PDB 2KD3; Weidauer SE, Schmieder P, Beerbaum M, Schmitz W, Oschkinat H, Mueller TD (February 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.
- ^ 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 (Feb 2001). "Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein". Am J Hum Genet 68 (3): 577–89. doi:10.1086/318811. PMC 1274471. PMID 11179006. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1274471.
- ^ 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 (Feb 2001). "Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST)". Hum Mol Genet 10 (5): 537–43. doi:10.1093/hmg/10.5.537. PMID 11181578.
- ^ "Entrez Gene: SOST sclerosteosis". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=50964.
- ^ Krumlauf and Ellies US 60/388,970, filed 04.06.2002
- ^ Li X, Zhang Y, Kang H, Liu W, Liu P, Zhang J, Harris SE, Wu D (May 2005). "Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling". J. Biol. Chem. 280 (20): 19883–7. doi:10.1074/jbc.M413274200. PMID 15778503.
- ^ van Bezooijen RL, Svensson JP, Eefting D, Visser A, van der Horst G, Karperien M, Quax PH, Vrieling H, Papapoulos SE, ten Dijke P, Löwik CW (January 2007). "Wnt but not BMP signaling is involved in the inhibitory action of sclerostin on BMP-stimulated bone formation". J. Bone Miner. Res. 22 (1): 19–28. doi:10.1359/jbmr.061002. PMID 17032150.
- ^ 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 (December 2010). "Distinct modes of inhibition by sclerostin on bone morphogenetic protein and Wnt signaling pathways". J. Biol. Chem. 285 (53): 41614–26. doi:10.1074/jbc.M110.153890. PMID 20952383.
- ^ http://users.telenet.be/zeldzame.ziekten/List.o/Pmenoposteo.htm
- ^ Paszty C, Turner CH, Robinson MK (September 2010). "Sclerostin: a gem from the genome leads to bone-building antibodies". J. Bone Miner. Res. 25 (9): 1897–904. doi:10.1002/jbmr.161. PMID 20564241.
- ^ Rey JP, Ellies DL (January 2010). "Wnt modulators in the biotech pipeline". Dev. Dyn. 239 (1): 102–14. doi:10.1002/dvdy.22181. PMC 3111251. PMID 20014100. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=3111251.
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, et al. (2002). "Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease.". J. Med. Genet. 39 (2): 91–7. doi:10.1136/jmg.39.2.91. PMC 1735035. PMID 11836356. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1735035.
- Staehling-Hampton K, Proll S, Paeper BW, et al. (2002). "A 52-kb deletion in the SOST-MEOX1 intergenic region on 17q12-q21 is associated with van Buchem disease in the Dutch population.". Am. J. Med. Genet. 110 (2): 144–52. doi:10.1002/ajmg.10401. PMID 12116252.
- Balemans W, Foernzler D, Parsons C, et al. (2003). "Lack of association between the SOST gene and bone mineral density in perimenopausal women: analysis of five polymorphisms.". Bone 31 (4): 515–9. doi:10.1016/S8756-3282(02)00844-X. PMID 12398949.
- Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=139241.
- Clark HF, Gurney AL, Abaya E, et al. (2003). "The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment.". Genome Res. 13 (10): 2265–70. doi:10.1101/gr.1293003. PMC 403697. PMID 12975309. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=403697.
- Winkler DG, Sutherland MK, Geoghegan JC, et al. (2004). "Osteocyte control of bone formation via sclerostin, a novel BMP antagonist.". EMBO J. 22 (23): 6267–76. doi:10.1093/emboj/cdg599. PMC 291840. PMID 14633986. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=291840.
- Sevetson B, Taylor S, Pan Y (2004). "Cbfa1/RUNX2 directs specific expression of the sclerosteosis gene (SOST).". J. Biol. Chem. 279 (14): 13849–58. doi:10.1074/jbc.M306249200. PMID 14739291.
- van Bezooijen RL, Roelen BA, Visser A, et al. (2004). "Sclerostin is an osteocyte-expressed negative regulator of bone formation, but not a classical BMP antagonist.". J. Exp. Med. 199 (6): 805–14. doi:10.1084/jem.20031454. PMC 2212719. PMID 15024046. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2212719.
- Winkler DG, Yu C, Geoghegan JC, et al. (2004). "Noggin and sclerostin bone morphogenetic protein antagonists form a mutually inhibitory complex.". J. Biol. Chem. 279 (35): 36293–8. doi:10.1074/jbc.M400521200. PMID 15199066.
- Zhang Z, Henzel WJ (2005). "Signal peptide prediction based on analysis of experimentally verified cleavage sites.". Protein Sci. 13 (10): 2819–24. doi:10.1110/ps.04682504. PMC 2286551. PMID 15340161. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2286551.
- Sutherland MK, Geoghegan JC, Yu C, et al. (2005). "Sclerostin promotes the apoptosis of human osteoblastic cells: a novel regulation of bone formation.". Bone 35 (4): 828–35. doi:10.1016/j.bone.2004.05.023. PMID 15454089.
- Gerhard DS, Wagner L, Feingold EA, et al. (2004). "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).". Genome Res. 14 (10B): 2121–7. doi:10.1101/gr.2596504. PMC 528928. PMID 15489334. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=528928.
- Uitterlinden AG, Arp PP, Paeper BW, et al. (2005). "Polymorphisms in the sclerosteosis/van Buchem disease gene (SOST) region are associated with bone-mineral density in elderly whites.". Am. J. Hum. Genet. 75 (6): 1032–45. doi:10.1086/426458. PMC 1182139. PMID 15514891. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1182139.
- Winkler DG, Sutherland MS, Ojala E, et al. (2005). "Sclerostin inhibition of Wnt-3a-induced C3H10T1/2 cell differentiation is indirect and mediated by bone morphogenetic proteins.". J. Biol. Chem. 280 (4): 2498–502. doi:10.1074/jbc.M400524200. PMID 15545262.
- Poole KE, van Bezooijen RL, Loveridge N, et al. (2006). "Sclerostin is a delayed secreted product of osteocytes that inhibits bone formation.". FASEB J. 19 (13): 1842–4. doi:10.1096/fj.05-4221fje. PMID 16123173.
- Gardner JC, van Bezooijen RL, Mervis B, et al. (2006). "Bone mineral density in sclerosteosis; affected individuals and gene carriers.". J. Clin. Endocrinol. Metab. 90 (12): 6392–5. doi:10.1210/jc.2005-1235. PMID 16189254.
- Ellies DL, Viviano B, McCarthy J, et al. (2007). "Bone density ligand, Sclerostin, directly interacts with LRP5 but not LRP5G171V to modulate Wnt activity.". J. Bone Miner. Res. 21 (11): 1738–49. doi:10.1359/jbmr.060810. PMID 17002572.
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