GENETIC ANALYSIS OF BONE MORPHOGENETIC PROTEINS

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The long term goal of this research is to define the molecular mechanisms that control growth and patterning of cartilage, bone, and joint. This is a general proble, in the developent of higher animals, and is of particular relevance to the understanding and treatment of human skeletal diseases, including osteoporosis and osteoarthritis. The studies are specifically directed to understanding the role of bone morphogenetic proteins (BMPs) in normal development. BMPs were originally isolated based on their remarkable ability to induce new caritlage and bone formation when implanted under the skin of animals. The vertebrae genome contains ten or more BMP genes, each expressed in different patterns during normal development. Closely related genes are found in many other organisms, where they control a wide variety of functions, including axis formation, tissue differentiation, and epithelial- mesenchymal interactions. While BMPs are now recognized as one of key classes of signalling molecules in animal development, the large number of different BMPs, and their multiple functions, has hampered studies of their specific role in skeletal development. We have recently shown that two classical mouse genes (short ear and brachypodism) encode two different members of the BMP family. Defects in these genes produce surprisingly specific alterations in particular bone and cartilage elements, and in particular joints. Based on the mutant phenotypes and wxpression patterns of these genes, we have proposed that bMps are the endogenous signals used by embryos to induce the formation of both bones and joints, and that different members of the BMP family control the formation of different sets of skeletal structures. To test this model, we will use two different genetic strategies to examine the functions of other Bmps in mouse development. A dominant negative nutaton will be used to inactivate multiple BMPs in specific skeletal tissues. Knowckout mutations in two new Bmps will be used to test whether different BMPs control formation of different types of joints. Finally, we will use transgenic mice and novel regulatory mutations to define the cis and trans acting factors that control where and when particular bone and joint inducing signals are expressed during normal development. These studies will provide new insights into the basic biological mechanisms that create bones and joints, new tools for maipulating gene expression at specific sites in the skeleton, and may suggest novel strategies for modulating BMP expression in human skeletal diseases.