Bone growth in children 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. This research focuses on understanding the chondrocytic differentiation cascade in relationship to growth. The long term objective is to understand the interrelationships among multiple controls, acting through systemic, paracrine, and autocrine mechanisms that are responsible for coordinated long bone growth from embryonic life through adolescence, and to analyze perturbations of growth with the intent of designing and implementing optimal strategies for managing the correction of abnormalities of long bone growth. Using an approach of quantitative measurement of multiple chondrocytic kinetic parameters that completely describe the dynamics of cellular contributions to growth, the Specific Aims of the current proposal are: To test the hypothesis that patterns of differential growth characteristic of specific bones are absent prenatally, but are established starting in the perinatal period and become well defined during early postnatal development, and that this translation is reflected in different cellular control mechanisms; To test the hypothesis that postnatal bone elongation occurs by a pattern of brief intense growth saltations followed by much longer periods of no growth (stasis); To test the hypothesis that the primary action of growth hormone, either circulating systemically or delivered locally, is to increase all rate-dependent phases of chondrocytic differentiation during the postnatal period, thus accelerating rates of differential growth and increasing growth velocity; To test the hypothesis that decreased rate of growth following minimal total nutritional deprivation postnatally, as well as catch-up growth following return to normal nutritional status, are controlled through altering the rate at which chondrocytes at all levels of the growth plate proceed through the differentiation cascade, amplified by volume changes at the level of the hypertrophic chondrocyte.
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