Transcriptional Regulation of Osteocalcin Production by Transforming Growth Factor-β in Rat Osteoblast-Like Cells

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Abstract
Osteocalcin (OC) is one of the abundant noncollagenous bone matrix proteins produced exclusively by osteoblasts, and its serum level is used an an indicator of bone metabolism in patients. Transforming growth factor-.beta. (TGF.beta.) is abundant in bones and platelets, promotes wound healing in vivo, and is a potent stimulator of the production of extracellular matrix proteins in fibroblasts and osteoblasts. The effects of TGF.beta. on OC gene expression were examined in rat osteoblast-like cells, ROS17/2.8. TGF.beta.1 decreased OC levels in the culture media 2- to 3-fold. TGF.beta.1 also decreased the level of osteocalcin mRNA about 3-fold in a dose-dependent manner. TGF.beta.2 and TGF.beta.1,2, a heterodimeric form, showed similar effects on OC mRNA levels as TGF.beta.1. The suppression of the OC message level was detectable at 24 h and lasted for up to 72 h. This effect on OC mRNA was blocked by cycloheximide. The stability of OC mRNA was not changed by TGF.beta.1. On the other hand, the rate of OC gene transcription was reduced 4- to 5-fold, as estimated by in vitro nuclear transcription (run-on) assay. TGF.beta.1 blocked the increase in the OC mRNA level induced by PTH or 1,25-dihydroxyvitamin D3. These results indicate that TGF.beta. inhibits osteocalcin gene expression at least in part through transcriptional control.