Regulation of Skeletal Growth

我们继续探索控制骨骼生长和发育的细胞和分子机制，并应用这些信息来改善生长障碍和儿童代谢性骨病的医学治疗。我们发现骨形态发生蛋白-2 （BMP-2）通过三种机制调节生长板软骨形成和纵向骨生长：增加生长板软骨细胞增殖、增加软骨细胞肥大和增加软骨基质合成。在其他研究中，我们发现有证据表明生长板的正常衰老过程不是时间的函数，而是生长板软骨细胞所经历的累积复制次数的函数。骨骺融合（生长板消失）发生在衰老后期，此时生长板软骨细胞的增殖潜能已经耗尽。糖皮质激素过量抑制软骨细胞增殖，减缓衰老程序，并延迟骨骺融合。相反，雌激素似乎加速衰老程序，从而加速骨骺融合。这些发现可以解释某些临床现象，如生长抑制后的追赶生长和雌激素暴露后的过早骨骺融合。在正在进行的临床研究中，我们正在调查阿仑膦酸钠治疗骨质疏松症儿童和生长激素治疗非生长激素缺乏患者的安全性和有效性。对后一项研究数据的中期分析表明，与之前的报告相反，生长激素不会改变男孩青春期发育的时间或速度。

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.