Transcriptional regulation of osteocalcin production by transforming growth factor-beta in rat osteoblast-like cells.
Osteocalcin (OC) is one of the abundant non-collagenous bone matrix proteins produced exclusively by osteoblasts, and its serum level is used as 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.
Department of Bone Biology and Osteoporosis Research, Merck, Sharp, and Dohme Research Laboratories, West Point, Pennsylvania 19486.
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D000818:Animals; D015152:Blotting, Northern; D001842:Bone and Bones / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000235:genetics*; D002460:Cell Line; D005786:Gene Expression Regulation / Q000187:drug effects*; D005796:Genes; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism*; D015675:Osteocalcin; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics*; D051381:Rats; D014158:Transcription, Genetic / Q000187:drug effects*; D015291:Transforming Growth Factors / Q000494:pharmacology*
D002135:Calcium-Binding Proteins; D012333:RNA, Messenger; D015675:Osteocalcin; D015291:Transforming Growth Factors