Featured Investigator and Recipient of a Pilot and Feasibility Project Award
Michael Centrella, Ph.D is a Professor in the Department of Surgery, Yale University School of Medicine.
Our group examines mechanisms that control growth factor and growth factor receptor expression and activity in osteoblasts. Growth factors that control bone formation also affect other tissues. Therefore, we proposed that other local and systemic agents regulate them in a tissue-specific way. Our goal is to determine how these events converge on cells within the osteoblast lineage.
We found that certain TGF-b receptor subtypes vary during osteoblast differentiation or in response to other factors that control osteoblast function. When this occurs, TGF-b activity increases, decreases, or induces only discrete molecular events. To study TGF-b receptor expression, we cloned the gene promoters for the rat TGF-b type I, type II, and type III receptors (TRI, TRII and TRIII).
We found that TRI gene promoter activity is partly controlled by a tissue-restricted transcription factor termed Runx2, which itself increases with osteoblast differentiation.Glucocorticoid potently suppresses Runx2 protein in osteoblasts in parallel with decreases in TRI expression and TGF-b activity. Importantly, loss of Runx2 by genetic mutation severely compromises bone formation. We hypothesize that this occurs in part through a decrease in the stimulatory effect of TGF-b on bone matrix protein synthesis, and that pathological bone loss with glucocorticoid excess may reprise this in a hormone-dependent way. In contrast, PGE2 activates endogenous Runx2 and increases Runx2-dependent gene expression in a protein kinase (PK)-dependent way. We are now studying how glucocorticoid targets Runx2 for proteolysis, and which Runx2 domains are sensitive to PK activation. In addition, we are defining the cis-acting elements that regulate TRII and TRIII expression in response to osteoblast differentiation and hormones that control osteoblast activity.
We use a similar approach to understand IGF-I expression and activity in bone. Here, we identified a nuclear factor termed C/EBPd that controls IGF-I expression in response to PGE2, estradiol, and glucocorticoid. We found that these hormones can control IGF-I gene expression indirectly in osteoblasts through changes in C/EBPd expression or its ability to bind DNA. We recently reported that Runx2 also regulates C/EBPd expression by osteoblasts, and that high levels of C/EBPd eventually suppress Runx2 activity. Therefore, we defined novel intracellular loops of positive and negative feed-back control between these several important transcription factor systems that regulate osteoblast growth factor and growth factor receptor expression.
- McCarthy, T. L., C. Ji, M. Centrella (2000) Links among growth factors, hormones, and nuclear factors with essential roles in bone formation. Critical Rev. Oral Biol. Med. 11:409-422.
- McCarthy, T. L., C. Ji, Y. Chen, K. K. Kim, M. Imagawa, Y. Ito, M. Centrella (2000) Runt domain factor (Runx)-dependent effects on CCAAT/enhancer binding-protein d expression and activity in osteoblasts. J. Biol. Chem. 275:21746-21753.