Abstract
Recent studies implicate the transforming growth factor beta (TGF-β) superfamily as playing a major role in bone formation. Nothing is currently known about the function of vgr-1 (also called Bone Morphogenetic Protein-6, or BMP-6), a TGF-β-like protein that localizes to hypertrophic cartilage. To determine if this factor enhances chondrocytic differentiation and/or stimulates osteogenesis, we have utilized two pluripotent mesenchymal cell lines, C3H-10T1/2 and ROB-C26. Stable trans-fectants that over-express vgr-1 mRNA were created with each cell line. Such over-expression does not alter the growth rate of the two cell lines. Vgr-1 over-expression results in up to a 9-fold increase in alkaline phosphatase(ALP) activity in C26 cells, but has no significant effect on 10TI/2 cells. In the presence of 10−6M retinoic acid (RA), an osteoinductive agent, C26 and 10T1/2 parental cells as well as the 10T1/2 vgr-1 over-expressors exhibit a stimulation in enzyme activity; by contrast, C26 vgr-1 over-expressors consistently show a decrease in ALP activity relative to untreated vgr-1 over-expressors. To determine if vgr-1's osteoinductive effects are mediated through a feedback mechanism involving changes in the extracellular matrix(ECM), we have grown parental and vgr-1-transfected C26 cells on plastic, then removed the over-lying cells, and replated parental cells back onto the various underlying residual ECMs. The ECM from vgr-3 transfeetants induces up to 4-fold greater ALP activity than the ECM of parental cells; such induction was not seen with ECM from RA-treated C26 vgr-1 over-expressors. These results suggest that; 1) vgr-1 induces osteogenic differentiation, and that this effect is mediated through changes in the ECM composition; 2)vgr-1 over-expression inhibits RA induction of alkaline phosphatase activity in C26 but not in 10T1/2 cells. Ongoing studies will determine vgr-1's effects on other markers of both bone and cartilage differentiation in these cell lines, through in vitro and in vivo analyses.
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