Regulation of Skeletal Growth

骨骼生长的调节

• 批准号: 6108021
• 负责人: Jeffrey Baron
• 金额: --
• 依托单位: EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6108021
• 关键词: autosomal dominant trait; bone development; bone metabolism; cartilage; child (0-11); clinical research; developmental genetics; endocrinology; fibroblast growth factor; gene mutation; glucocorticoids; hormone receptor; hormone regulation /control mechanism; human subject; hypercalciuria; hypoparathyroidism; kidney cell; messenger RNA; neuroendocrine system; normal ossification; organ culture; osteocytes; parathyroid gland; receptor expression; somatotropin

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.

我们发现了Ca 2+敏感基因的突变， 甲状旁腺功能减退症患者的受体基因。我们有 表明这些突变可以与 常染色体显性遗传家系疾病 或在散发性疾病患者中重新出现。当 在培养的细胞中表达，这些突变引起了 通过增加对钙的敏感性， 最大的信号转导能力。我们还研究了 哺乳动物纵向骨生长的调节。我们展示 禁食会迅速降低纵向骨生长和生长 体内接骨板宽度。这种生长抑制似乎并不 由局部生长板胰岛素样生长因子-I介导 （IGF-I）系统，其被上调。相反， 伴随全身IGF-I系统的下调。生长板 软骨和邻近的骨表现出空间极性。通过 操纵生长板内的空间关系， 已经表明生长板软骨的极性是由 内在因素。软骨极性决定了 相邻骨的极性，因此， 纵向骨生长的极性。其他研究探讨了 成纤维细胞生长因子-2，类维生素A，C型利钠肽， 和cGMP在细胞增殖和分化调节中的作用 在生长板。治疗试验使用生长激素或IGF-I 治疗极端矮小的研究正在进行中。我们 开始使用阿仑膦酸钠进行额外的临床试验， 来治疗儿童骨质疏松症。