Bone growth in children and adolescent animals occurs by endochondral ossification in cartilaginous growth plates at the ends of long bones. In any given growth plate, chondrocytes occur in a characteristic spatial organization that also is a representation of the temporal progression of individual chondrocytic differentiation. A unique aspect of the differentiation process of the growth plate chondrocyte is the translation of this differentiation into growth. This research focuses on understanding the biology of growth plate cartilage in relationship to growth. The long-term objective of this research is to understand the multiple control mechanisms involved in regulating the rate and extent of long bone growth from embryonic patterning, to interactions of chondrocytes with their matrix to initiate/cease specific gene expression, to systemic hormonal controls, to local paracrine, autocrine and biomechanical controls over growth plate activity. The specific objective of this proposal is to understand control mechanisms, acting at the level of the chondrocyte, that are responsible for coordinated long bone growth in multiple growth plates within the person/animal at one point in time, and in one growth plate over time. This objective is extended to include understanding of perturbations of normal growth with the intent of understanding the possibilities and limitations of intervention procedures for the correction of abnormalities of long bone growth. Using a variety of in situ based microscopical, stereological, and experimental techniques, the four Specific Aims of our current proposal are: 1. To test the hypothesis that variables associated with cell cycle parameters of chondrocytes within the proliferative zone are significant determinants of the variability in rate of growth of different growth plates. 2. To test the hypothesis that overall growth is controlled by volume changes translated into appropriate cellular shape changes during hypertrophy. 3. To test the hypothesis that control points for the regulation of growth occur at specific transition points. 4. To test the hypothesis the alterations of rate of growth achieved by externally mediated perturbations are controlled at the level of the hypertrophic chondrocyte.
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