Repetitive exposure to TGF-β suppresses TGF-β type I receptor expression by differentiated osteoblasts

Transforming growth factor-beta (TGF-beta) has potent, cell phenotype restricted effects. In bone, it controls multiple activities by osteoblasts through three predominant receptors. Of these, the relative amounts of TGF-beta receptor I (T beta RI) vary directly with TGF-beta sensitivity. The rat T beta RI gene promoter includes cis-acting elements for transcription factor Runx2. Here we show conservation and selective partitioning of T beta RI and retention of TGF-beta activity with osteoblast differentiation, Runx2 binding to the T beta RI gene promoter on osteoblast chromatin, and decreased promoter activity by Runx2 binding site mutation. Furthermore, in contrast to the stimulatory effects induced by single or limited exposure to TGF-beta, we found that osteoblasts became resistant to TGF-beta after high dose and repetitive treatment. T beta RI protein, mRNA, and gene-promoter activity all decreased after. three daily TGF-beta treatments, in parallel with a reduction in Runx2 protein and Runx dependent gene expression. In this way, sustained TGF-beta exposure can limit its own effectiveness by suppressing the expression of its primary signaling receptor. This tightly controlled system may constitute a feedback loop to protect against TGF-beta excess, and impose important limitations that are required for the progression of events during skeletal growth, remodeling and repair. (c) 2006 Elsevier B.V. All rights reserved.