REGULATION AND FUNCTIONAL ANALYSIS OF TYPE X COLLAGEN

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The primary objective of this proposal is to study the regulation and function of type X collagen, a member of a subfamily of short chain collagens, during the development of the mammalian skeletal system. During endochondral ossification (EO), chondrocytes undergo a series of transitions including proliferation, maturation, hypertrophy, and death. Deposition of extracellular matrix proteins during this precisely regulated differentiation pathway results in the production of hypertrophic cartilage that forms the substrate for calcification and bone deposition. Type X collagen is expressed abundantly and specifically in hypertrophic chondrocytes suggesting that this matrix protein plays a critical role in skeletal formation. Recent findings support this idea, however the true in vivo function of this molecule during mammalian skeletal development is unknown. We are interested in addressing basic questions in mammalian skeletal development that center around type X collagen. How is the gene activated? What is this matrix protein's required function during development? How does the production of abnormal type X collagen result in disease? Does ectopic expression of wild-type protein lead to disease? We propose genetic experiments in vivo to answer these questions. Indeed, we have already generated type X collagen-null mice. The mutant animals have allowed us to directly study the requirement of this extracellular matrix protein during the development of the mammalian skeletal system. The information generated from our proposal studies should provide fundamental information about type X collagen regulation and function.