The TGF-β superfamily is a large family of structurally related dimeric growth and differentiation factors. Depending on the nature of the factor and the cell type, these factors induce changes in cell proliferation, synthesis of extracellular matrix components, cell-matrix interactions and expression of differentiation-specific markers. In addition to these activities, the expression of the TGF-β superfamily members at sites of cellular differentiation during development implicates these proteins as important mediators of cell differentiation and tissue development. We have concentrated on the role of distinct members of the TGF-β superfamily in the differentiation of mesenchymal cells into muscle, bone and cartilage cells. Our general approach to define the function of these factors in mesenchymal differentiation is to alter the expression levels of either the ligands or the corresponding receptors and to evaluate the consequences for cellular differentiation both in vitro and in vivo.

In one set of studies, we have evaluated the role of endogenous TGF-β responsiveness in the maintenance of the differentiated phenotype of myoblasts and osteoblasts. We therefore abrogated the responsiveness to TGF-β in established osteoblasts and myoblasts that can differentiate into myoutubes in culture. Our results indicate an important role of continuous TGF-β responsiveness in these well-differentiated cell types. In other studies we focussed on the biological activities of vgr-l/BMP-6, a TGF-β family member which is specifically expressed in hypertrophic cartilage, but for which no functional information is as yet available. Transfected CHO cells overexpressing murine vgr-1/BMP-6 were derived and recombinant vgr-1/BMP-6 was purified to serve as a source of the factor thus allowing us to evaluate its role in osteogenesis and chondrogenesis in culture. In addition, transfected CHO cells overexpressing vgr-1/BMP-6 were inoculated into mice and the effect of vgr-1/BMP-6 on the phenotype of the resulting tumors was evaluated by histological analysis. Studies of this type should allow us to define the natural role of the different TGF-β family members in the mesenchymal differentiation pathways.

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Derynck, R., Filvaroff, E., Erlebacher, A. et al. THE ROLE OF TGF-β FAMILY MEMBERS IN MESENCHYMAL DIFFERENTIATION. Pediatr Res 33, S9–S10 (1993).

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