Bone Abstracts

Sclerostin, encoded by the SOST gene, functions as an inhibitor of the Wnt pathway and thus it is an important regulator of bone homeostasis. The fact that osteoblasts, the only cells expressing SOST, lay buried deeply in the bone matrix, poses intrinsic difficulties to the study of the regulation of this gene. Since RUNX2 and SP7/OSX are two known regulators of the differentiation of cells of the osteoblastic lineage, the aim of this study was to determine their potential role in the regulation of human SOST.

Chromatin immunoprecipitation experiments performed with osteoblast-like cells expressing sclerostin confirmed that both RUNX2 and OSX bound to the SOST promoter in a position closely located to the transcription start site. Using a luciferase reporter system containing the SOST promoter region, we showed that both RUNX2 and OSX significantly increased the expression of the SOST gene. Interestingly, we also observed an additive effect when cells were transfected with both expression vectors simultaneously. Moreover, when the expression of these genes was measured in human bone samples, we found significant correlations between SOST and RUNX2 expression (r=0.47, P=0.03), and between SOST and OSTERIX (r=0.55, P=0.01) expression, but not between RUNX2 and OSX (P=0.19, P=0.43). These results further support a crucial role of RUNX2 and OSX in the activation of human SOST.

In a genetic association study, two polymorphisms of the promoter region of the RUNX2 gene were significantly associated with BMD in a group of 987 postmenopausal women (P=0.02). However, we did not find statistically significant interactions between them and other OSX and SOST polymorphisms on bone mineral density.

In summary, the transcription factors encoded by RUNX2 and SP7/OSX bind to the human SOST promoter, stimulate SOST expression in vitro and are likely regulators of sclerostin production in human bone.