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

6. TGF- BETA RECEPTORS

On osteoblasts,TGF-beta binds to high affinity receptors like those found on many other cells (11,31). Studies in chemically mutated mink lung epithelial cells implicated TGF-beta receptor I [TGF-betaRI of 53 kDa] and TGF-beta receptor II [TGF-betaRII of 75 kDa] in signal transduction (32). Different mutant mink lung cells were then isolated that express various levels of TGF-beta receptors. When intact or mutant TGF-beta receptors were transfected back into the mutated cells, TGF-beta appears first to bind TGF-betaRII. This complex can recruit TGF-betaRI, which itself also associates directly with TGF-beta. In this context, the kinase domain of TGF-betaRII phosphorylates TGF-betaRI, and downstream signals follow (33-36). Thus, TGF-betaRI is indispensable for TGF-beta activity. TGF-beta also binds with lower affinity to proteoglycans of >250 kDa, first termed TGF-beta type III receptors [TGF-betaRIII], but now also called betaglycans (37-39). Cell surface betaglycans do not themselves initiate a biochemical event, but may facilitate extracellular storage of TGF-beta, control its activation, or regulate its binding to other TGF-beta receptors (40,41). Consequently, the proportion rather than the actual amount of each of TGF-beta receptor may determine the extent of ligand binding in total, or it may focus TGF-beta to inactive, potentially active, or active receptors or receptor complexes (21). Receptors for several of the TGF-beta supergene family members appear similar to TGF-betaRI and/or TGF-betaRII. While interactions between TGF-betaRI, TGF-betaRII and receptors for other TGF-beta supergene family members have been reported in reconstituted cell models, homologous ligand/receptor binding appears to be specific in the normal situation (42-51). For example, bone cells express receptors for several TGF-beta supergene family members, but they preferentially bind TGF-beta at conventional TGF-betaRI, TGF-betaRII, and betaglycan (11,21,23,45). Other less well characterized TGF-beta receptors (20,31) have not been reported on osteoblasts. Again, many studies including those in bone predict changes in TGF-beta receptors during development, aging, or in response to specific hormones (11,19,21,52-58).

The cDNAs for TGF-betaRI, TGF-betaRII, and betaglycan core protein, all prominently expressed by bone cells, are cloned (33,36,46,59-61), and specific antibodies are available to evaluate changes in TGF-beta protein. However, to understand how the expression of genes encoding the TGF-beta receptors are controlled during bone development, remodeling, and disease, promoter analysis is essential. Until recently only the TGF-betaRII promoter was cloned (62,63). Because TGF-betaRI is maintained with bone cell differentiation (21) and is the essential component for all known TGF-beta dependent effects (31), our lab cloned the rat TGF-betaRI promoter (64) to assess cis- and trans-acting elements that regulate TGF-betaRI synthesis by bone cells. Aspects of these studies are described later in this review.