TRANSFORMING GROWTH-FACTOR-BETA-1 INHIBITS COLLAGENASE-3 EXPRESSION BY TRANSCRIPTIONAL AND POSTTRANSCRIPTIONAL MECHANISMS IN OSTEOBLAST CULTURES

Transforming growth factor (TGF) beta 1 is an autocrine regulator of b one cell function. We demonstrated that TGF beta 1 enhances bone colla gen synthesis, but its effects on collagen degradation are not well ch aracterized We tested the effects of TGF beta 1 on rat collagenase 3 e xpression in cultures of osteoblast-enriched cells from fetal rat calv ariae (Ob cells). Treatment with TGF beta 1 at 0.4 nM decreased steady state collagenase mRNA levels after 2 to 24 h. This dose-dependent ef fect was observed at TGF beta 1 concentrations of 4 pM to 1.2 nM, and was accompanied by decreased levels of immunoreactive procollagenase. The protein synthesis inhibitor cycloheximide increased collagenase tr anscripts, but did not prevent the effect of TGF beta 1 on collagenase mRNA levels. TGF beta 1 accelerated the decay of collagenase mRNA in transcriptionally arrested Ob cells. In addition, TGF beta 1 decreased the levels of collagenase heterogeneous nuclear RNA and the rate of c ollagenase gene transcription in Ob cells. TGF beta 1 enhanced the exp ression of tissue inhibitors of metalloproteinases (TIMP) 1 and 3 and caused a modest decrease of TIMP 2 mRNA levels. in conclusion, TGF pi decreases interstitial collagenase transcripts and protease levels in Ob cells by transcriptional and post-transcriptional mechanisms, and t his effect may contribute to its actions on bone matrix. (C) 1997 Wile y-Liss, inc.