Repetitive exposure to TGF-beta suppresses TGF-beta 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 (TbetaRI) vary directly with TGF-beta sensitivity. The rat TbetaRI gene promoter includes cis-acting elements for transcription factor Runx2. Here we show conservation and selective partitioning of TbetaRI and retention of TGF-beta activity with osteoblast differentiation, Runx2 binding to the TbetaRI 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. TbetaRI 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.
Kim
Kenneth K
KK
Yale University School of Medicine, Department of Surgery, New Haven, CT 06520-8041, USA.
Ji
Changhua
C
Chang
Weizhong
W
Wells
Rebecca G
RG
Gundberg
Caren M
CM
McCarthy
Thomas L
TL
Centrella
Michael
M
D030201:Activin Receptors, Type I / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism; D015870:Gene Expression; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D050659:Core Binding Factor Alpha 1 Subunit; D018125:Receptors, Transforming Growth Factor beta; C493717:Runx2 protein, rat; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D030201:Activin Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625843:Tgfbr1 protein, rat