EFFECTS OF GLUCOCORTICOIDS AND IGF 1 ON BONE FORMATION

骨质疏松症通常是糖皮质激素治疗的结果， 内源性糖皮质激素水平的病理状态 都被提升了。糖皮质激素引起的骨质疏松症是由于 骨吸收增加，骨形成减少。 糖皮质激素是骨形成的重要调节剂， 然而，它们的影响往往是自相矛盾的。虽然生理学上 糖皮质激素浓度促进成骨细胞分化 在颅骨和骨髓基质细胞的原代培养中， 药物浓度通过以下途径抑制骨形成 成骨细胞更新和功能减弱。胰岛素样生长 然而，因子I(IGF-I)是骨形成的合成代谢。已经过去了 以前已经证明IGF-I可以防止抑制 糖皮质激素对胎鼠颅骨器官培养的影响。在……里面 这项提议，我们将利用转基因方法来 设计新的、更明确的评估效果的策略 GCS和IGF-I在骨形成中的相互作用。首先，它是 假设IGF-I在骨骼中的过度表达将增加 预防骨质疏松症的形成和抑制作用 体内的糖皮质激素。第二，建议将IGF-I归零 小鼠在骨形成方面会有缺陷，并容易患上 糖皮质激素对骨形成的抑制作用。第三，它 假设在体内糖皮质激素会限制 骨髓基质细胞体外成骨分化的实验研究 通过耗尽祖先的骨髓来培养文化。这些假设 将通过以下模式解决：a 将开发出独特的转基因小鼠，其中IGF-I COL1A1启动子特异定位于骨的表达 在骨骼中高表达但在大多数其他组织中不表达的片段 纸巾。胎儿IGF-I基因缺失小鼠颅骨器官培养 被研究。最后，小鼠接受糖皮质激素治疗。 体内与体外骨髓基质细胞的分化 在体外进行培养检查。这些研究将在以下方面提供见解 糖皮质激素和胰岛素样生长因子-I在骨和骨骼上的相互作用 在小鼠体内靶向表达生长因子是否会 预防糖皮质激素对骨的抑制作用 队形。

Osteoporosis is often a consequence of glucocorticoid therapy and pathological conditions in which endogenous glucocorticoid level are elevated. Glucocorticoid induced osteoporosis is due to an increase of bone resorption and a decrease in bone formation. Glucocorticoids are important regulators of bone formation, although, their effects are often paradoxical. While physiologic concentrations of glucocorticoids promote osteoblast differentiation in primary cultures of calvarial and bone marrow stromal cells, pharmacological concentrations inhibit bone formation by decreasing osteoblast renewal and function. Insulin-like growth factor I (IGF-I), however, is anabolic for bone formation. It been have previously shown that IGF-I can prevent the inhibitory effects of glucocorticoids in organ cultures of fetal rat calvaria. In this proposal, we will take advantage of transgenic approaches to design new and more definitive strategies for assessing the effects and interactions of Gcs and IGF-I on bone formation. First, it is hypothesize that overexpression of IGF-I in bone will increase bone formation and prevent the inhibitory effects of glucocorticoids in vivo. Second, it is suggested that IGF-I null mice will have defects in bone formation and will be susceptible to the inhibitory effects glucocorticoids on bone formation. Third, it is hypothesized that in vivo glucocorticoids willlimit the osteogenic differentiation of ex vivo bone marrow stromal cell cultures by depleting the marrow of progenitors. These hypotheses will be addressed will be addressed with the following models: A unique trans-genic mouse will be developed in which IGF-I expression is specifically targeted to bone by a COL1A1 promoter fragment that is highly expressed in bone but not most other tissues. Organ cultures of calvaria from fetal IGF-I null mice will be studied. Finally, mice with be treated with glucocorticoids in vivo and the differentiation of ex vivo bone marrow stromal cell cultures examined in vitro. These studies will provide insights in to the interactions of glucocorticoids and IGF-I on bone and show whether or not targeted growth factor expression in mice will prevent the inhibitory effects of glucocorticoids on bone formation.