Received date: 2013-01-28
Revised date: 2013-06-14
Online published: 2013-08-25
Sclerostin(SOST), mainly expressed in osteocytes, is a negative regulator of bone formation. Hormones PTH and E2 inhibit the expression of the SOST gene. Transcription factors Osterix, Runx2, and Mef2c promote the SOST expression, while Sirt1 negatively regulates the SOST expression. In addition, the expression of the SOST gene is regulated by epigenetic mechanisms, such as DNA methylation and microRNA. Mutations in the SOST gene, which cause sclerosteosis and Van Buchem diseases, are associated with osteoporosis. Wnt and BMP are two important signaling pathways in bone metabolic regulation. SOST can regulate osteoblastic differentiation and bone formation by binding type I/II receptors and co-receptor LRP5/6 to inhibit BMP and Wnt signaling pathways. Suppression of SOST provides a new approach for osteoporosis treatment. This review covers the structure, function and expression regulation of the SOST gene, human disease association, mechanism in the regulation of bone metabolism and prospect in clinical application.
Key words： SOST gene; osteoporosis; bone; sclerostin; gene expression
QIN Long-Juan, DING Da-Xia, CUI Lu-Lu, HUANG Qing-Yang . Expression and regulation of the SOST gene[J]. Hereditas(Beijing), 2013 , 35(8) : 939 -947 . DOI: 10.3724/SP.J.1005.2013.00939
[1] Van Hul W, Balemans W, Van Hul E, Dikkers FG, Obee H, Stokroos RJ, Hildering P, Vanhoenacker F, Van Camp G, Willems PJ. Van Buchem disease (hyperostosis corticalis generalisata) maps to chromosome 17q12-q21. Am J Hum Genet, 1998, 62(2): 391-399.
[2] Balemans W, Van Den Ende J, Paes-Alves AF, Dikkers FG, Willems PJ, Vanhoenacker F, de Almeida-Melo N, Alves CF, Stratakis CA, Hill SC, Van Hul W. Localization of the gene for sclerosteosis to the van Buchem disease-gene re-gion on chromosome 17q12-q21. Am J Hum Genet, 1999, 64(6): 1661-1669.
[3] 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, Fo-ernzler D, Van Hul W. Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST). Hum Mol Genet, 2001, 10(5): 537-543.
[4] Brunkow ME, Gardner JC, Van Ness J, Paeper BW, Kovacevich BR, Proll S, Skonier JE, Zhao L, Sabo PJ, Fu YH, Alisch RS, Gillett L, Colbert T, Tacconi P, Galas D, Hamersma H, Beighton P, Mulligan J. Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein. Am J Hum Genet, 2001, 68(3): 577-589.
[5] Poole KE, van Bezooijen RL, Loveridge N, Hamersma H, Papapoulos SE, Löwik CW, Reeve J. Sclerostin is a delayed secreted product of osteocytes that inhibits bone formation. FASEB J, 2005, 19(13): 1842-1844.
[6] Mayor C, Brudno M, Schwartz JR, Poliakov A, Rubin EM, Frazer KA, Pachter LS, Dubchak I. VISTA: visualizing global DNA sequence alignments of arbitrary length. Bio-informatics, 2000, 16(11): 1046-1047.
[7] Balemans W, Van Hul W. Human genetics of SOST. J Musculoskelet Neuronal Interact, 2006, 6(4): 355-356.
[8] Pearce JJ, Penny G, Rossant J. A mouse cerberus/Dan-related gene family. Dev Biol, 1999, 209(1): 98-110.
[9] Hsu DR, Economides AN, Wang XR, Eimon PM, Harland RM. The Xenopus dorsalizing factor Gremlin identifies a novel family of secreted proteins that antagonize BMP ac-tivities. Mol Cell, 1998, 1(5): 673-683.
[10] Veverka V, Henry AJ, Slocombe PM, Ventom A, Mulloy B, Muskett EW, Muzylak M, Greenslade K, Moore A, Zhang L, Gong JH, Qian XM, Paszty C, Taylor RJ, Robinson MK, Carr MD. Characterization of the structural features and interactions of sclerostin: molecular insight into a key regulator of Wnt-mediated bone formation. J Biol Chem, 2009, 284(16): 10890-10900.
[11] Weidauer SE, Schmieder P, Beerbaum M, Beerbaum M, Schmitz W, Oschkinat H, Mueller TD. NMR structure of the Wnt modulator protein sclerostin. Biochem Biophys Res Commun, 2009, 380(1): 160-165.
[12] Loots GG. Kneissel M, Keller H, Baptist M, Chang J, Collette NM, Ovcharenko D, Plajzer-Frick I, Rubin EM. Genomic deletion of a long-range bone enhancer mis-regulates sclerostin in Van Buchem disease. Genome Res, 2005, 15(7): 928-935.
[13] Li X, Ominsky MS, Niu QT, Sun N, Daugherty B, D'Agostin D, Kurahara C, Gao Y, Cao J, Gong J, Asuncion F, Barrero M, Warmington K, Dwyer D, Stolina M, Morony S, Sarosi I, Kostenuik PJ, Lacey DL, Simonet WS, Ke HZ, Paszty C. Targeted deletion of the sclerostin gene in mice results in increased bone formation and bone strength. J Bone Miner Res, 2008, 23(6): 860-869.
[14] Li X, Ominsky MS, Warmington KS, Morony S, Gong J, Cao J, Gao Y, Shalhoub V, Tipton B, Haldankar R, Chen Q, Winters A, Boone T, Geng Z, Niu QT, Ke HZ, Kostenuik PJ, Simonet WS, Lacey DL, Paszty C. Sclerostin antibody treatment increases bone formation, bone mass, and bone strength in a rat model of postmenopausal osteoporosis. J Bone Miner Res, 2009, 24(4): 578-588.
[15] Ominsky MS, Vlasseros F, Jolette J, Smith SY, Stouch B, Doellgast G, Gong J, Gao Y, Cao J, Graham K, Tipton B, Cai J, Deshpande R, Zhou L, Hale MD, Lightwood DJ, Henry AJ, Popplewell AG, Moore AR, Robinson MK,
/
| 〈 |
|
〉 |
www.chinagene.cn
备案号：京ICP备09063187号
