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Gene Review

SOST  -  sclerostin

Homo sapiens

Synonyms: CDD, SOST1, Sclerostin, UNQ2976/PRO7455/PRO7476, VBCH
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Disease relevance of SOST


High impact information on SOST

  • SOST expression was detected in cultured osteoblasts and in mineralizing areas of the skeleton, but not in osteoclasts [6].
  • The clinical and radiographic stigmata of sclerosteosis permit differentiation from the other disorders of the "osteopetrosis" or "Albers-Schönberg disease" group, in which bony thickening and cranial nerve palsy occur [5].
  • We studied whether the sclerosteosis/van Buchem disease gene (SOST) is an osteoporosis-risk gene by examining its association with bone-mineral density (BMD) [7].
  • We used a set of eight polymorphisms from the SOST gene region to genotype 1,939 elderly men and women from a large population-based prospective-cohort study of Dutch whites [7].
  • Mutations in SOST result in sclerosteosis, and alterations in the SOST gene expression may be causal in the closely related van Buchem disease [7].

Chemical compound and disease context of SOST


Biological context of SOST

  • In Xenopus and mammalian cell culture assays, we showed that SOST is able to attenuate Wnt signaling and that this attenuation can be rescued by the addition of alpha-Sost antibodies or by the introduction of single amino acid substitution that alter its binding to LRP6 [8].
  • SOST, a novel bone morphogenetic protein (BMP) antagonist and negative regulator of bone formation, is expressed in osteogenic cells [9].
  • We did not find association between any of several frequent haplotypes across the SOST gene region and BMD [7].
  • A 3-bp insertion (f=0.38) in the presumed SOST promoter region (SRP3) was associated with decreased BMD in women at the femoral neck (FN) (P=.05) and lumbar spine (LS) (P=.01), with evidence of an allele-dose effect in the oldest age group (P=.006) [7].
  • A null mutation in the SOST gene is associated with sclerosteosis, an inherited disorder characterized by a high bone mass phenotype [10].

Anatomical context of SOST


Associations of SOST with chemical compounds

  • BMP's stimulatory effects on SOST were further enhanced by retinoic acid or 1,25-dihydroxyvitamin D3 [9].
  • In contrast, dexamethasone (DEX) blocked the effects of the BMPs on SOST and gremlin, but not on noggin [9].
  • We compared and contrasted the mechanism of action for the cysteine knot protein subfamily, Wise and Sost (Sclerostin) [8].
  • The conserved N- and C-terminal arms of sclerostin were found to be unstructured, highly flexible, and unaffected by heparin binding, which suggests a role in stabilizing interactions with target proteins [14].

Physical interactions of SOST

  • LRP5 Mutations Linked to High Bone Mass Diseases Cause Reduced LRP5 Binding and Inhibition by SOST [15].

Other interactions of SOST

  • A 52-kb deletion in the SOST-MEOX1 intergenic region on 17q12-q21 is associated with van Buchem disease in the Dutch population [16].
  • Downregulation of SOST/Sclerostin by PTH: A novel mechanism of hormonal control of bone formation mediated by osteocytes [17].
  • Sclerosteosis shares remarkable similarities with "high bone mass" diseases caused by "gain-of-function" mutations in the LRP5 gene, which encodes a coreceptor for Wnt signaling proteins [11].

Analytical, diagnostic and therapeutic context of SOST


  1. Cbfa1/RUNX2 directs specific expression of the sclerosteosis gene (SOST). Sevetson, B., Taylor, S., Pan, Y. J. Biol. Chem. (2004) [Pubmed]
  2. A generalized skeletal hyperostosis in two siblings caused by a novel mutation in the SOST gene. Balemans, W., Cleiren, E., Siebers, U., Horst, J., Van Hul, W. Bone (2005) [Pubmed]
  3. Too much bone: the middle ear in sclerosing bone dysplasias. Hamersma, H., Hofmeyr, L. Adv. Otorhinolaryngol. (2007) [Pubmed]
  4. Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein. Brunkow, M.E., Gardner, J.C., Van Ness, J., Paeper, B.W., Kovacevich, B.R., Proll, S., Skonier, J.E., Zhao, L., Sabo, P.J., Fu, Y., Alisch, R.S., Gillett, L., Colbert, T., Tacconi, P., Galas, D., Hamersma, H., Beighton, P., Mulligan, J. Am. J. Hum. Genet. (2001) [Pubmed]
  5. The clinical features of sclerosteosis. A review of the manifestations in twenty-five affected individuals. Beighton, P., Durr, L., Hamersma, H. Ann. Intern. Med. (1976) [Pubmed]
  6. Osteocyte control of bone formation via sclerostin, a novel BMP antagonist. Winkler, D.G., Sutherland, M.K., Geoghegan, J.C., Yu, C., Hayes, T., Skonier, J.E., Shpektor, D., Jonas, M., Kovacevich, B.R., Staehling-Hampton, K., Appleby, M., Brunkow, M.E., Latham, J.A. EMBO J. (2003) [Pubmed]
  7. Polymorphisms in the sclerosteosis/van Buchem disease gene (SOST) region are associated with bone-mineral density in elderly whites. Uitterlinden, A.G., Arp, P.P., Paeper, B.W., Charmley, P., Proll, S., Rivadeneira, F., Fang, Y., van Meurs, J.B., Britschgi, T.B., Latham, J.A., Schatzman, R.C., Pols, H.A., Brunkow, M.E. Am. J. Hum. Genet. (2004) [Pubmed]
  8. Bone Density Ligand, Sclerostin, Directly Interacts With LRP5 but Not LRP5(G171V) to Modulate Wnt Activity. Ellies, D.L., Viviano, B., McCarthy, J., Rey, J.P., Itasaki, N., Saunders, S., Krumlauf, R. J. Bone Miner. Res. (2006) [Pubmed]
  9. Unique regulation of SOST, the sclerosteosis gene, by BMPs and steroid hormones in human osteoblasts. Sutherland, M.K., Geoghegan, J.C., Yu, C., Winkler, D.G., Latham, J.A. Bone (2004) [Pubmed]
  10. Sclerostin promotes the apoptosis of human osteoblastic cells: a novel regulation of bone formation. Sutherland, M.K., Geoghegan, J.C., Yu, C., Turcott, E., Skonier, J.E., Winkler, D.G., Latham, J.A. Bone (2004) [Pubmed]
  11. SOST is a ligand for LRP5/LRP6 and a Wnt signaling inhibitor. Semënov, M., Tamai, K., He, X. J. Biol. Chem. (2005) [Pubmed]
  12. SOST expression is restricted to the great arteries during embryonic and neonatal cardiovascular development. van Bezooijen, R.L., Deruiter, M.C., Vilain, N., Monteiro, R.M., Visser, A., van der Wee-Pals, L., van Munsteren, C.J., Hogendoorn, P.C., Aguet, M., Mummery, C.L., Papapoulos, S.E., Ten Dijke, P., Löwik, C.W. Dev. Dyn. (2007) [Pubmed]
  13. Parathyroid hormone - a bone anabolic and catabolic agent. Poole, K.E., Reeve, J. Current opinion in pharmacology. (2005) [Pubmed]
  14. Characterization of the structural features and interactions of sclerostin: molecular insight into a key regulator of Wnt-mediated bone formation. Veverka, V., Henry, A.J., Slocombe, P.M., Ventom, A., Mulloy, B., Muskett, F.W., Muzylak, M., Greenslade, K., Moore, A., Zhang, L., Gong, J., Qian, X., Paszty, C., Taylor, R.J., Robinson, M.K., Carr, M.D. J. Biol. Chem. (2009) [Pubmed]
  15. LRP5 Mutations Linked to High Bone Mass Diseases Cause Reduced LRP5 Binding and Inhibition by SOST. Semenov, M.V., He, X. J. Biol. Chem. (2006) [Pubmed]
  16. A 52-kb deletion in the SOST-MEOX1 intergenic region on 17q12-q21 is associated with van Buchem disease in the Dutch population. Staehling-Hampton, K., Proll, S., Paeper, B.W., Zhao, L., Charmley, P., Brown, A., Gardner, J.C., Galas, D., Schatzman, R.C., Beighton, P., Papapoulos, S., Hamersma, H., Brunkow, M.E. Am. J. Med. Genet. (2002) [Pubmed]
  17. Downregulation of SOST/Sclerostin by PTH: A novel mechanism of hormonal control of bone formation mediated by osteocytes. Bellido, T. Journal of musculoskeletal & neuronal interactions (2006) [Pubmed]
  18. Lack of association between the SOST gene and bone mineral density in perimenopausal women: analysis of five polymorphisms. Balemans, W., Foernzler, D., Parsons, C., Ebeling, M., Thompson, A., Reid, D.M., Lindpaintner, K., Ralston, S.H., Van Hul, W. Bone (2002) [Pubmed]
  19. Endocrine function in sclerosteosis. Epstein, S., Hamersma, H., Beighton, P. S. Afr. Med. J. (1979) [Pubmed]
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