Sclerostin in Mineralized Matrices and van Buchem Disease

Abstract

Sclerostin is an inhibitor of bone formation expressed by osteocytes. We hypothesized that sclerostin is expressed by cells of the same origin and also embedded within mineralized matrices. In this study, we analyzed (a) sclerostin expression using immunohistochemistry, (b) whether the genomic defect in individuals with van Buchem disease (VBD) was associated with the absence of sclerostin expression, and (c) whether this was associated with hypercementosis. Sclerostin was expressed by cementocytes in mouse and human teeth and by mineralized hypertrophic chondrocytes in the human growth plate. In individuals with VBD, sclerostin expression was absent or strongly decreased in osteocytes and cementocytes. This was associated with increased bone formation, but no overt changes in cementum thickness. In conclusion, sclerostin is expressed by all 3 terminally differentiated cell types embedded within mineralized matrices: osteocytes, cementocytes, and hypertrophic chondrocytes.

Get full access to this article

View all access options for this article.

References

Balemans W, Ebeling M, Patel N, Van Hul E, Olson P, Dioszegi M, et al. -2001-. Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein -SOST-. Hum Mol Genet 10: 537–543.

Balemans W, Patel N, Ebeling M, Van Hul E, Wuyts W, Lacza C, et al. -2002-. Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease. J Med Genet 39:91–97.

Balemans W, Cleiren E, Siebers U, Horst J, Van Hul W -2005-. A generalized skeletal hyperostosis in two siblings caused by a novel mutation in the SOST gene. Bone 36:943–947.

Beighton P -1988-. Sclerosteosis. J Med Genet 25:200–203.

Beighton P, Barnard A, Hamersma H, van der Wouden A -1984-. The syndromic status of sclerosteosis and van Buchem disease. Clin Genet 25:175–181.

Bellido T, Ali AA, Gubrij I, Plotkin LI, Fu Q, O’Brien CA, et al. -2005-. Chronic elevation of parathyroid hormone in mice reduces expression of sclerostin by osteocytes: a novel mechanism for hormonal control of osteoblastogenesis. Endocrinology 146:4577–4583.

Brunkow ME, Gardner JC, Van Ness J, Paeper BW, Kovacevich BR, Proll S, et al. -2001-. Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein. Am J Hum Genet 68:577–589.

Ellies DL, Viviano B, McCarthy J, Rey JP, Itasaki N, Saunders S, et al. -2006-. Bone density ligand, sclerostin, directly interacts with LRP5 but not LRP5-G171V- to modulate Wnt activity. J Bone Miner Res 21:1738–1749.

Epstein S, Hamersma H, Beighton P -1979-. Endocrine function in sclerosteosis. S Afr Med J 55:1105–1110.

10.

Hamersma H, Gardner J, Beighton P -2003-. The natural history of sclerosteosis. Clin Genet 63:192–197; erratum in Clin Genet 64:176, 2004.

11.

Irie K, Ejiri S, Sakakura Y, Shibui T, Yajima T -2008-. Matrix mineralization as a trigger for osteocyte maturation. J Histochem Cytochem 56:561–567.

12.

Leucht P, Minear S, ten Berge D, Nusse R, Helms JA -2008-. Translating insights from development into regenerative medicine: the function of Wnts in bone biology. Semin Cell Dev Biol 19:434–443.

13.

Li X, Zhang Y, Kang H, Liu W, Liu P, Zhang J, et al. -2005-. Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling. J Biol Chem 280:19883–19887.

14.

Li X, Ominsky MS, Niu QT, Sun N, Daugherty B, D’Agostin D, et al. -2008-. Targeted deletion of the sclerostin gene in mice results in increased bone formation and bone strength. J Bone Miner Res 23:860–869.

15.

Loots GG, Kneissel M, Keller H, Baptist M, Chang J, Collette NM, et al. -2005-. Genomic deletion of a long-range bone enhancer misregulates sclerostin in Van Buchem disease. Genome Res 15:928–935.

16.

Poole KE, van Bezooijen RL, Loveridge N, Hamersma H, Papapoulos SE, Lowik CW, et al. -2005-. Sclerostin is a delayed secreted product of osteocytes that inhibits bone formation. FASEB J 19:1842–1844.

17.

Semenov M, Tamai K, He X -2005-. SOST is a ligand for LRP5/LRP6 and a Wnt signaling inhibitor. J Biol Chem 280:26770–26775.

18.

Semenov MV, He X -2006-. LRP5 mutations linked to high bone mass diseases cause reduced LRP5 binding and inhibition by SOST. J Biol Chem 281:38276–38284.

19.

Staehling-Hampton K, Proll S, Paeper BW, Zhao L, Charmley P, Brown A, 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 110:144–152.

20.

Stephen LX, Hamersma H, Gardner J, Beighton P -2001-. Dental and oral manifestations of sclerosteosis. Int Dent J 51:287–290.

21.

Truswell AS -1958-. Osteopetrosis with syndactyly; a morphological variant of Albers-Schonberg’s disease. J Bone Joint Surg Br 40-B-:209–218.

22.

van Bezooijen RL, Roelen BA, Visser A, van der Wee-Pals L, de Wilt E, Karperien M, et al. -2004-. Sclerostin is an osteocyte-expressed negative regulator of bone formation, but not a classical BMP antagonist. J Exp Med 199:805–814.

23.

van Bezooijen RL, ten Dijke P, Papapoulos SE, Lowik CWGM -2005-. SOST/sclerostin, an osteocyte-derived negative regulator of bone formation. Cytokine Growth Factor Rev 16:319–327.

24.

van Bezooijen RL, Svensson JP, Eefting D, Visser A, van der Horst G, Karperien M, et al. -2007-. Wnt but not BMP signaling is involved in the inhibitory action of sclerostin on BMP-stimulated bone formation. J Bone Miner Res 22:19–28.

25.

van Bezooijen RL, Papapoulos SE, Hamdy NAT, Lowik CWGM -2008-. SOST/sclerostin; an osteocyte-derived inhibitor of bone formation that antagonizes canonical Wnt signaling. In: Principles of bone biology. 3^rd ed. Raisz LG, Martin TJ, Bilezikian JP, editors. New York: Academic Press, pp. 139–152.

26.

van Buchem FS, Hadders HN, Ubbens R -1955-. An uncommon familial systemic disease of the skeleton: hyperostosis corticalis generalisata familiaris. Acta Radiol 44:109–120.

27.

Winkler DG, Sutherland MK, Geoghegan JC, Yu C, Hayes T, Skonier JE, et al. -2003-. Osteocyte control of bone formation via sclerostin, a novel BMP antagonist. EMBO J 22:6267–6276.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.76 MB