Differential effects of transforming growth factor-beta 1 and bone morphogenetic protein 4 on gene expression and differentiated function of preosteoblasts.

Abstract

Transforming growth factor-beta (TGF-beta) and bone morphogenetic protein 4 (BMP 4) are both able, under certain circumstances, to induce endochondral bone formation in vivo. This study compared the effects of TGF-beta 1 and BMP 4 on the gene expression of a retinoic acid (RA) responsive rat clonal preosteoblast cell line, UMR 201, as well as the way in which these proteins interact with RA in these cells. Both similarities as well as differences between the effects and mechanism of action of TGF-beta 1 and BMP 4 were demonstrated. TGF-beta 1 (0.1 ng/ml) strongly induced matrix gla protein (MGP) mRNA and increased the steady state osteonectin (ON) mRNA level. Cotreatment with TGF-beta 1 and RA did not result in a further increase in MGP mRNA expression. In contrast, BMP 4 alone had no influence on MGP or ON mRNA expression but it significantly enhanced the RA induction of MGP mRNA. Pro-alpha 1(l) collagen mRNA was increased by TGF-beta 1 (1 ng/ml) and BMP 4 (50 ng/ml). The addition of either TGF-beta 1 or BMP 4 together with RA resulted in a further increase in pro-alpha 1 (l) collagen mRNA levels. Both RA and TGF-beta 1, but not BMP 4, increased the transcriptional rate of the pro-alpha 1 (l) collagen gene. TGF-beta 1 reduced the constitutive as well as RA-induced expression of osteopontin (OP) mRNA while BMP 4 reduced only the constitutive expression of OP mRNA. RA increased the transcriptional rate of the OP gene. Since the responses of UMR 201 cells to these structurally related factors were not identical, the results lend support to the concept that the coordinated expression of members of the TGF-beta 1 superfamily may be necessary to control the progression of specific cell types through their differentiation pathways.