Bone Morphogenetic Proteins (BMPs) are essential regulators of osteogenesis. At least 9 different BMPs induce ectopic bone formation, and most of these proteins are expressed in skeletal tissues. BMP3, a divergent member of the BMP family, is one of the most abundant BMPs in adult bone, yet little is known about its function as a regulator of osteogenic commitment/ differentiation. Recently, BMP3b, a gene closely related to BMP3, has been described. The expression of multiple members of the BMP family in bone suggests that either BMPs serve overlapping functions, or that individual BMPs play distinct roles in cartilage and bone. The goal of this proposal is to investigate the roles of BMP3 and BMP3b in osteogenic commitment/ differentiation. Preliminary results from Xenopus assays show that BMP3 has unique effects compared to those of osteogenic BMPs. Preliminary in vitro data show that BMP3 and BMP3b have either positive or negative effects on osteogenic differentiation, depending on the context of expression. Therefore, our [the applicants'] results indicate that BMP3 and BMP3b may have antagonistic effects on osteogenic differentiation, suggesting that the roles of BMP3 and BMP3b in vivo may be to modulate levels of bone formation. In order to test this hypothesis, BMP3 mutant mice have been generated. BMP 3-/-mice will be analyzed on a morphological, histological, radiological and biomechanical level. Preliminary results suggest that BMP3 negatively regulates bone density in vivo. To test whether BMP3 and BMP3b may have overlapping functions in osteogenesis, expression patterns for BMP3 and 3b will be analyzed. To test genetically whether BMP3b affects bone physiology in vivo, BMP3b-/- mice will be generated. To test whether BMP3 and 3b have overlapping functions in skeletal tissues, compound BMP3/BMP3b mutants will be examined. The abilities of BMP3 and BMP3b to modify the effects of other BMPs will be examined. Because the preliminary data indicate that BMP3 and BMP3b, which are abundant in adult bone, may have either positive or negative effects in vitro, in vivo tests of function, such as the analysis of targeted strains of mice, are essential to understanding the role these growth factors play in adult bone. It is suggested that this information will contribute to our overall understanding of the roles of BMPs in osteogenic precursor cells, and may suggest potential therapies for conditions, such as arthritis and osteoporosis, based on augmentation or inhibition of BMP3 activity.
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