During endochondral ossification, chondrocytes of the cartilaginous growth plate are found in a spatial gradient of cellular maturation beginning with cellular proliferation and ending with cellular hypertrophy. The focus of this study is chondrocytic hypertrophy -- its contribution to overall bone growth during normal endochondral ossification, its significance in post-natal diseases of long bone growth, and its potential as a component of long bone growth which can be manipulated for the correction of angular deformities or limb anisomelia. The long term objective is to understand what controls the magnitude of chondrocytic hypertrophy as this relates to the rate of overall bone growth, as well as the control by these cells in directing the progress of metaphyseal cellular elements. This relates directly to an understanding of the pathogenesis of a wide variety of growth plate disorders characterized by both abnormal chondrocytic hypertrophy and subsequent failure of metaphyseal vascular penetration. The primary focus is on the osteochondroses, which currently are classified as over 50 different disease entities of the growth plate, named by anatomical location. Using morphological criteria from video-enhanced rectified interference contrast microscopy of living organ cultures, vital dye binding and lectin binding of living chondrocytes in situ, improved chemical fixation for light and selectron microscopy, and stereology, the three specific aims of the current proposal are: 1. To test the hypothesis that the process of cellular hypertrophy is controlled at three critical transition points. It is hypothesized that the hypertrophic cell zone does not consist of a continuum of cellular maturation in which each cell can be uniquely defined, but rather that the hypertrophic cell zone has three distinct subzones characterized by definable maturational stages. 2. To test the hypothesis that hypertrophic cell volume correlates positively with the of growth of a given growth plate. This hypothesis will be tested by using computerized serial section reconstructions and newly developed stereological techniques on a series of growth plates from multiple species, growing at different rates. 3, To test the hypothesis that hypertrophic cell volume is influenced by externally mediated perturbations which are known to alter the rate of long bone growth. The model will be the spontaneous correction of experimentally induced angular limb deformities.
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