Long bone growth results from a delicately synchronized sequence of events involving the differentiation of three groups of specialized chondrocytes. The ultimate chondrocyte is greatly hypertrophied and is believed to direct the invasion of capillaries and subsequent calcification. In rats that are deficient in vitamin D and phosphate, these events are reversibly altered, capillary invasion is reduced and the growth plate becomes greatly expanded; this model allows for (1) biochemical analysis of the cell types that make up the growth plate and (2) induction of capillary invasion and calcification by treatment with vitamin D and phosphate. The central premise of these studies is that hypertrophic chondrocytes are responsible for directing calcification and, in particular, the directed migration of capillary endothelial cells. The presence of various growth factors known to induce or regulate endothelial cell chemotaxis, such as acidic fibroblast growth factors (aFGF), basic fibroblast growth factor (bFGF), platelet derived growth factor (PDGF, transforming growth factor- beta-1 (TGF-beta-1), and endothelial cell stimulating angiogenesis factor (ESAF), will be determined. Studies will be performed on tissues, cell or organ cultures, and co-cultures. Growth factor localization and characterization will be based on the results of endothelial cell chemotaxis assays of extracted tissues and culture media after heparin- Sepharose chromatography, Western blots of isolated growth factors and immunolocalization with specific antibodies. Relative mRNA levels for each growth factor will be determined by Northern analysis. Reversal of rickets (induction of capillary invasion) by vitamin D, its metabolites, and PTH will be used to study growth factor regulation. The overall goal of the research program is to elucidate the final common pathways leading to osteoarthritis (OA) which may be amenable to therapeutic intervention. Articular cartilage injury may initiate a cascade of events that result in increased metalloproteinase production, followed by a change in joint congruity. These changes result in small endochondral growth centers (i.e.: hypertrophic spurs) beneath the articular cartilage which appear very similar to growth plate and which result in a narrowing of the hyaline cartilage. With increased understanding of how growth plate calcification occurs, it is hoped that additional sites for therapeutic intervention in OA will be found.
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