Regulation of gastric and osteoclast acidification by Snx10

 描述(申请人提供)：骨质疏松症的健康和经济影响继续使破骨细胞骨吸收的研究成为一个至关重要的研究重点。破骨细胞特别依赖于囊泡运输，这是骨吸收所必需的。因此，破骨细胞囊泡运输的中断(遗传或药理学)取消了吸收活性。已知SNX家族的蛋白调节内体的分选、内吞作用、膜蛋白的循环，以及不同的内体和高尔基体之间的运输。我们发现了Snx10，这是一个在破骨细胞和胃中表达的家族成员，它是产生酸性物质所必需的。我们通过基因捕获技术获得了Snx10基因缺陷小鼠(Snx10ins/ins)，并对其骨表型进行了鉴定。Snx10ins/ins小鼠表现出一种复杂的表型，它是骨化病(由于破骨细胞吸收受损)和软骨病(由于胃酸和钙吸收障碍导致的矿化受损)的组合，称为骨角膜炎。导致骨质疏松症的潜在机制目前尚不清楚。基于这些发现，我们得出结论，Snx10通过调节破骨细胞和胃中的囊泡运输和酸的产生，对体内的骨稳态是必不可少的。在这项提案中，我们将利用骨骼和胃中细胞特异性的Snx10消融研究来阐明Snx10调节破骨细胞吸收和胃酸化以实现骨稳态的分子机制。这一建议具有很高的意义，因为它将表征一个新的候选基因，该基因参与了人类骨病的发展，包括骨质疏松症和与缺钙相关的骨丢失。这些结果将改变Snx10和其他具有相似表达和活动模式的基因突变的骨化患者的治疗范式，这些患者的胃缺陷通常被忽视。重要的是，我们的发现将极大地促进我们对控制破骨细胞功能和胃肠道控制骨稳态的分子机制的理解。

 DESCRIPTION (provided by applicant): The health and economic impact of osteoporosis continues to make studies of bone resorption by osteoclasts a critically important research focus. Osteoclasts are exceptionally dependent on vesicular trafficking, which is essential for bone resorption. Consequently, disruption (genetic or pharmacological) of osteoclastic vesicle transport abolishes resorptive activity. Proteins of the Snx family are known to mediate endosomal sorting, endocytosis, recycling of membrane proteins, and trafficking between various endosomes and Golgi apparatus. We found Snx10, a family member expressed in osteoclasts and in the stomach, where it is required for acid production. We generated Snx10-deficient mice (Snx10ins/ins) via gene-trap technology and characterized the bone phenotype. Snx10ins/ins mice exhibit a complex phenotype that is a combination of osteopetrosis (due to impaired osteoclast resorption) and rickets (impaired mineralization due to impaired gastric acidification and poor calcium absorption) known as osteopetrorickets. The underlying mechanisms leading to osteopetrorickets are currently unknown. Based on these findings, we conclude that Snx10 is essential for bone homeostasis in vivo by regulating vesicular trafficking and therefore acid production in both osteoclasts and the stomach. In this proposal we will use cell-specific Snx10 ablation studies in bone and stomach to elucidate the molecular mechanisms by which Snx10 regulates both osteoclastic resorption and gastric acidification for bone homeostasis. This proposal has high significance as it will characterize a new candidate gene involved in the development of human bone diseases, including osteoporosis, and bone loss associated with calcium deficiency. These results will change the paradigm of therapy for osteopetrotic patients with mutations in Snx10 and other genes with similar patterns of expression and activities, whose gastric defect has been generally overlooked. Importantly, our findings will significantly advance our understanding of the molecular mechanisms controlling osteoclast function and the control of bone homeostasis by the gastrointestinal tract.