Proteoglycans are essential extracellular components for normal development and maintenance of cartilage tissue. This has been most convincingly demonstrated by studies on certain mutant model systems which exhibit altered cartilage development and/or organization resulting in abnormal growth patterns. In two particular model systems, which we have examined, defects have been localized exclusively to the pathway of proteoglycan synthesis. Although the defects have been conclusively identified in these two cases, the relationship between abnormal proteoglycan production and aberrant growth cannot yet be described. It is therefore our objective, through a multi-faceted approach, to use these animal model systems, 1) to correlate the biochemical defect with abnormal biological function, 2) to study the regulation of gene expression during cartilage differentiation in the abnormal situations, 3) to attempt to ameliorate the biological effect of the defect in the mutant animals and 4) to extend these animal studies to the heterogeneous group of human disorders, the skeletal dysplasias, some of which may have associated proteoglycan deficiencies. To accomplish this objective, a comprehensive research plan to characterize the defective protein molecules that have been identified in these two mutant systems, at the molecular and genetic level is described. Methodology to be employed includes all of the biochemical, immunological, histological, and molecular approaches is current use for the preceeding studies of this proposal and for other projects in our program. A new approach to be developed during the future proposal is the generation of long-term chondrocyte cell lines from normal and mutant animal and human sources. These cell lines should prove valuable for our proposed studies and for others interested in cartilage differentiation and disorders. All of these studies should aid ultimately in the elucidation of certain human skeletal dysplasias about which virtually nothing is known at the molecular level, and open up a range of possibilities for studies on hormone or gene replacement therapy.
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