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

Transforming growth factor-β (TGF-β) 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-β receptor I (TβRI) vary directly with TGF-β sensitivity. The rat TβRI gene promoter includes cis-acting elements for transcription factor Runx2. Here we show conservation and selective partitioning of TβRI and retention of TGF-β activity with osteoblast differentiation, Runx2 binding to the TβRI 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-β, we found that osteoblasts became resistant to TGF-β after high dose and repetitive treatment. TβRI protein, mRNA, and gene promoter activity all decreased after three daily TGF-β treatments, in parallel with a reduction in Runx2 protein and Runx dependent gene expression. In this way, sustained TGF-β 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-β excess, and impose important limitations that are required for the progression of events during skeletal growth, remodeling and repair.