Somatomedin inhibitors are thought to antagonize somatomedin stimulated skeletal growth but may also be direct inhibitors of cartilage metabolism. We have isolated the predominant high MW inhibitor from rat liver; it produces reversible, dose-dependent inhibition of cartilage growth in embryonic chicken pelvic rudiment prolonged organ culture. We have named this factor """"""""chondrostatin"""""""" because it can reversibly inhibit both basal and serum or thyroid hormone stimulated cartilage growth. This study is designed to elucidate the biological and chemical properties of chondrostatin (CS) and to clarify the mechanism of action of this naturally occuring growth inhibitor. We plan to: 1) delineate the mechanism of growth inhibition by CS utilizing the embryonic chicken pelvic rudiment prolonged organ culture technique which allows direct measurements of overall growth of this skeletal organ and which allows study of the interaction of CS with the other cartilage growth factors through measurement of proteoglycan, DNA, protein synthesis and tissue histology; 2) define basic biochemical properties of CS through gel-filtration, gel electrophoresis, ion exchange and high pressure liquid chromotography in order to enhance our limited knowledge of the chemistry of CS and to potentially lead to the development of more precise assays; 3) study the action of CS directly on non-cartilage tissue (muscle and fat) to assess if it has broad anti-anabolic actions; 4) measure changes in CS levels during the induction of and recovery from diabetes or malnutrition to evaluate if poor growth in these conditions correlates with metabolically regulated CS levels; and 5) compare the potency of different somatomedin inhibitors with the chicken cartilage assay to obtain direct measurement of inhibitor effects on overall growth. The proposed study will provide valuable knowledge on the regulation of cartilage metabolism and growth.
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