Sclerostin is a secreted inhibitor of Wnt signaling and plays an essential role 
in the regulation of bone mass. The expression of sclerostin is largely 
restricted to osteocytes although its mode of transcriptional regulation is not 
well understood. We observed regulated expression of sclerostin mRNA and protein 
that was directly correlated with the mineralization response in cultured human 
Saos-2 osteosarcoma cells and rat primary calvarial cells. Sclerostin mRNA and 
protein levels were increased following treatment of cells with BMP2, BMP4 and 
BMP7. Analysis of deletion mutants from the -7.4 kb upstream region of the human 
sclerostin promoter did not reveal any specific regions that were responsive to 
BMPs, Wnt3a, PTH, TGFβ1 or Activin A in Saos-2 cells. The downstream ECR5 
element did not show enhancer activity in Saos-2 cells and also was not affected 
when Saos-2 cells were treated with BMPs or PTH. Genome-wide microarray analysis 
of Saos-2 cells treated with BMP2 showed significant changes in expression of 
several transcription factors with putative consensus DNA binding sites in the 
region of the sclerostin promoter. However, whereas most factors tested showed 
either a range of inhibitory activity (DLX family, MSX2, HEY1, SMAD6/7) or lack 
of activity on the sclerostin promoter including SMAD9, only MEF2B showed a 
positive effect on both the promoter and ECR5 element. These results suggest 
that the dramatic induction of sclerostin gene expression by BMPs in Saos-2 
cells occurs indirectly and is associated with late stage differentiation of 
osteoblasts and the mineralization process.