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

5. TGF-BETA SUPERGENE FAMILY AND BONE

Over 12 years ago, the growth factor isolated from rat bone culture medium, termed bone derived growth factor I, was identified as a homologue of TGF-beta type 1 (TGF-beta1) obtained from tumor extracts and blood platelets. Cartilage inducing factors from bovine bone were then recognized as TGF-beta isoforms, and it soon became clear that bone cells synthesize TGF-beta and that bone matrix is a major storage site for TGF-beta in the organism (20). The TGF-beta supergene family includes three isoforms of TGF-beta itself. Other less closely related gene family members are the bone morphogenetic proteins [BMPs]. The BMPs are stored in bone matrix and increase bone cell activity in vivo and in vitro, verifying a prominent role for TGF-betas and related molecules on bone formation (22-25). Many results now indicate independent roles for individual members of the TGF-beta supergene family and their receptors. The TGF-betas themselves are disulfide-linked dimers of 25 kilodaltons (kDa) (26,27). They are synthesized and released from cells in inactive complexes containing amino-terminal cleavage products, and in many cases, latent TGF-beta binding protein [LTBP]. LTBP is not found in medium from mouse bone cultures and may not be necessary for latency, but it could direct secreted TGF-beta to matrix storage pools (28,29). Latency might protect nascent TGF-beta from proteolysis and maintain a source of activatable TGF-beta. Activation of latent TGF-beta may be enzymatic. However, during bone resorption, TGF-beta might also be released from bone matrix and activated by the acidic micro-environment beneath the sealing zone of osteoclasts (26,30).