The interaction between cells and extracellular matrix (ECM) plays a critical role in cellular differentiation and in the response of cells to various growth and differentiation factors. Several soluble, secreted factors have the ability to modulate cellular interaction with the matrix and to influence the deposition of matrix proteins. As far as we know, the most potent and physiologically important of these factors are the members of the TGF-beta superfamily. This project will focus defining the biological activities and the physiological role of one of these members, vgr-1 (also named BMP-6). Based on structural considerations, vgr-1 is the most closely related to those members of the superfamily which have been named the """"""""Bone Morphogenetic Proteins"""""""" (BMPs). Among these, vgr-1/BMP-6, BMP-5 and OP-1/BMP-7 form a small subgroup on the basis of structural homology. Nothing definitive is as yet known about the function of any of these factors, but the results from localization studies during development suggest an involvement of the vgr-1 protein in osteogenic differentiation. Two specific approaches will be used to obtain insight into the roles of vgr-1. In one approach, we will generate a cell line which produces high levels of recombinant vgr-1 protein, purify the protein and use the purified protein to evaluate its effect, in vitro, on osteogenic differentiation and ECM deposition by two multipotential mesenchymal progenitor cell lines. The effects of exogenously added vgr-1 protein on bone and cartilage differentiation in the first branchial arch in organ culture will also be examined. In the second approach, we will modify the endogenous expression levels of vgr-1 mRNA in these same progenitor cell lines by introducing a vgr-1 expression vector. These vgr-1 producing cells will then be evaluated for changes in their differentiation status and ECM synthesizing activity both in vitro and in vivo. Alternatively, the effects of abolition of endogenous vgr-1 synthesis by antisense oligonucleotides will be evaluated in the organ culture. Together, these studies should provide insight into the normal physiological role of the vgr-1 protein in osteogenic differentiation and ECM synthesis and deposition.
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