CONTROL OF TGF-BETA RECEPTOR EXPRESSION IN BONE

Michael Centrella, Changhua Ji, Thomas L. McCarthy

Department of Surgery, Plastic Surgery Section, Yale University School of Medicine, 333 Cedar Street, PO Box 208041, New Haven, CT 06520-8041,

Received 12/1/97 Accepted 12/5/97

12. PERSPECTIVE

TGF-beta is abundant in bone and is a potent regulator of osteoblast activity. The TGF-beta receptor profile varies with the state of osteoblast differentiation. Notably, the proportion of TGF-betaRI fluctuates in response to important systemic and local agents, consistent with changes in osteoblast function. To understand this in molecular detail, the TGF-betaRI promoter was cloned, and found to contain several binding sequences for tissue-restricted transcription factors termed CBFa. Several labs have now shown enrichment for one CBFa subunit, CBFa1, with osteoblast differentiation. Loss of CBFa1 by gene elimination limits skeletal tissue formation essentially to chondrogenesis. Furthermore, initial evidence indicates specific variations in CBFa1 in response to positive and negative regulators of the osteoblast phenotype. Studies in nonskeletal cells predict important interactions between CBFa and other nuclear proteins, and regulation of CBFa activity by transcriptional and post-transcriptional events. Our observations revealing molecular links between CBFa1 and TGF-betaRI provide further evidence that TGF-beta is an important factor in osteogenesis. Changes in TGF-betaRI expression provide a tight and phenotype dependent gatekeeper system that controls how the effects of TGF-beta are perceived. New information to understand the normal mechanisms that control TGF-betaRI through CBFa1 expression and activity in bone cells will improve our understanding of its important role in skeletal tissue growth, remodeling and repair.