G蛋白GNAS通过调节铁代谢影响骨质疏松的机制研究

骨质疏松发病率和发病人数逐年增加，是老年患者致残和致死的主要原因之一，但现有治疗方案有诸多缺点。因此，我们迫切需要新的治疗骨质疏松症的药物和疗法。绝经、增龄等因素可导致继发性铁过载，从而引起骨质疏松症。GNAS是重要的信号转导蛋白，可转录翻译生成Gsα和XLαs。申请人前期阐明了XLαs通过抑制转铁蛋白的内吞作用调控铁代谢，而Gsα不具备些功能。课题组亦发现XLαs基因敲除小鼠中骨小梁的骨密度骨厚度显著降低，骨髓干细胞的成骨分化和破骨分化功能被影响，且骨质疏松疾病模型下，XLαs基因敲除小鼠的骨丢失程度更为明显。本项目拟通过特异性过表达XLαs或其N末端序列的转基因小鼠及骨髓干细胞，并采用铁过载及卵巢切除手术模拟疾病模型，研究XLαs蛋白和N末端片段在骨组织和骨髓干细胞中对铁代谢和骨质疏松的作用。此研究将可能为骨质疏松症治疗提供新策略，具有重要的临床应用意义。

Osteoporosis, an enormous and growing public health problem, is becoming increasingly prevalent with the aging of the world population. However, despite tremendous therapeutic advances on the treatment for osteoporosis, the current therapies and drugs still have many drawbacks and side-effects. Previous literatures identify iron overload caused by aging and postmenopause as a facilitator of osteoporosis. XLαs, encoded by GNAS, is partly identical to the α-subunit of the stimulatory G protein (Gsα), but the cellular actions of XLαs remain poorly defined. We discovered that XLαs, but not Gsα, regulates iron metabolism through mediating transferrin endocytosis. We also found that the ablation of XLαs significantly decreases trabecular bone thickness and density, inhibits osteogenic differentiation and promotes osteoclast differentiation, suggesting a role of XLαs in controlling bone homeostasis. We will further investigate the effects of XLαs and N-terminal-XLαs in iron metabolism and osteoporosis by utilizing conditional transgenic mouse models and bone marrow stem cells overexpressing XLαs or N-terminal-XLαs. Iron overload and ovariectomy models will be employed to mimic disease models. This study will bring keen insight into the mechanistic understanding of GNAS and osteoporosis, and might provide potential therapeutic strategies against osteoporosis.