Sclerostin: Current Knowledge and Future Perspectives

Abstract

In recent years study of rare human bone disorders has led to the identification of important signaling pathways that regulate bone formation. Such diseases include the bone sclerosing dysplasias sclerosteosis and van Buchem disease, which are due to deficiency of sclerostin, a protein secreted by osteocytes that inhibits bone formation by osteoblasts. The restricted expression pattern of sclerostin in the skeleton and the exclusive bone phenotype of good quality of patients with sclerosteosis and van Buchem disease provide the basis for the design of therapeutics that stimulate bone formation. We review here current knowledge of the regulation of the expression and formation of sclerostin, its mechanism of action, and its potential as a bone-building treatment for patients with osteoporosis.

Sclerostin

“…Sclerostin is the gene product of SOST, discovered in 2001 (19). Inactivating mutations of the gene lead to sclerosteosis, and deletions in noncoding regions downstream of the gene were identified in van Buchem disease.…”

“…Moreover, sclerostin is able to promote intracellular bone morphogenic protein 7 (BMP7) proteasomal degradation and thus antagonizes the BMP7 signaling pathway only in cells expressing both proteins (21). Present understanding of the regulation of SOST/ sclerostin expression by osteocytes is as yet incomplete (19). On the one hand, 1,25-dihydroxyvitamin D (calcitriol); glucocorticoids; TNF-␣; and probably also BMP2, 4, and 6 are able to stimulate SOST/sclerostin expression.…”

An auditory profile of sclerosteosis

“…Recent studies discovered that excessive bone formation was caused by defective activity of the sclerostin protein, which was a product of the SOST gene in chromosome 17q12-q21 (Hamersma & Hofmeyr, 2007;Moester et al, 2010). In sclerosteosis, five mutations had been identified.…”

“…In sclerosteosis, five mutations had been identified. Three of these mutations introduced a premature termination codon and the other two mutations interfered with the joining of the gene (the splice site mutation being IVS1+3 A→T) in sclerosteosis (Balemans et al, 2002;Moester et al, 2010). No mutations within this gene were present in Van Buchem disease.…”

“…Instead 35 kb downstream of the SOST gene a 52 kb deletion had been identified (Moester et al, 2010). This deletion contained managing elements for SOST transcription, having the ability to produce a phenotype closely approximating sclerosteosis (Moester et al, 2010).…”