We continue to explore the cellular and molecular mechanisms governing bone growth and development and to apply this information to improve medical treatment of growth disorders and childhood metabolic bone diseases. We found evidence that bone morphogenetic protein-2 (BMP-2) regulates growth plate chondrogenesis and thus longitudinal bone growth by three mechanisms: increased growth plate chondrocyte proliferation, increased chondrocyte hypertrophy, and increased cartilage matrix synthesis. In other studies, we have found evidence that the normal process of growth plate senescence is a function not of time but rather of the cumulative number of replications that the growth plate chondrocytes have undergone. Epiphyseal fusion (disappearance of the growth plate) occurs late in the senescence program when the proliferative potential of the growth plate chondrocytes has been exhausted. Glucocorticoid excess inhibits chondrocyte proliferation, slows the senescence program, and delays epiphyseal fusion. Conversely, estrogen appears to accelerate the senescence program and thus hastens epiphyseal fusion. These findings may explain certain clinical phenomena such as catch-up growth following growth inhibition and premature epiphyseal fusion following estrogen exposure.In ongoing clinical studies, we are investigating the safety and efficacy of alendronate in children with osteoporosis and of growth hormone treatment in non-growth hormone-deficient patients. An interim analysis of data from the latter study suggests that growth hormone, contrary to previous reports, does not alter the timing or pace of pubertal development in boys.
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