Regulation of Skeletal Growth

我们发现了钙离子感应的突变。 甲状旁腺功能减退症患者的受体基因。我们有 证明了这些突变可以与 常染色体显性遗传模式家系的疾病 或者可以在散发性疾病的患者中重新出现。什么时候 在培养的细胞中表达，这些突变导致激活 受体通过增加对钙的敏感性和增加 最大信号转导能力。我们还研究了 哺乳动物纵向骨生长的调控。我们展示了 禁食会迅速减少纵向骨骼的生长和生长 活体内的板宽。这种生长抑制似乎并不是 由局部、生长板胰岛素样生长因子-I介导 (IGF-I)系统被上调。相反，它被关联到 全身性IGF-I系统下调。生长板 软骨和邻近的骨显示出空间的极性。通过 通过操纵增长板块内的空间关系，我们 已经表明生长板软骨的极性是由 受内在因素的影响。然后软骨的极性决定了 相邻骨骼的极性，因此，功能性 纵向骨生长的极性。其他研究探索了这一角色 成纤维细胞生长因子-2，维甲酸，C型利尿肽， 和cGMP在细胞增殖分化调控中的作用 在生长板。使用生长激素或IGF-I的治疗试验 对于极矮身材的治疗正在进行中。我们是 开始一项额外的临床试验，使用阿仑磷酸钠，一种抑制剂 治疗儿童骨质疏松症。

We identified mutations in the Ca2+-sensing receptor gene in patients with hypoparathyroidism. We have demonstrated that these mutations can either cosegregate with the disease in families with an autosomal dominant inheritance pattern or can arise de novo in patients with sporadic disease. When expressed in cultured cells, these mutations caused activation of the receptor by increasing the sensitivity to calcium and increasing maximal signal transduction capacity.We have also studied the regulation of mammalian longitudinal bone growth. We showed that fasting rapidly decreases longitudinal bone growth and growth plate width in vivo. This growth inhibition does not appear to be mediated by the local, growth plate insulin-like growth factor-I (IGF-I) system which was up-regulated. Instead it was associated with down-regulation of the systemic IGF-I system.Growth plate cartilage and the adjacent bone exhibit spatial polarity. By manipulating the spatial relationships within the growth plate, we have shown that the polarity of growth plate cartilage is determined by intrinsic factors. The cartilage polarity then determines the polarity of the adjacent bone and, consequently, the functional polarity of longitudinal bone growth. Other studies explore the role of fibroblast growth factor-2, retinoids, C-type natiuretic peptide, and cGMP in the regulation of cell proliferation and differentiation in the growth plate.Treatment trials using growth hormone or IGF-I for the treatment of extreme short stature are underway. We are beginning an additional clinical trial using alendronate, an inhibitor of bone resorption, to treat pediatric osteoporosis.