Regulation of gastric and osteoclast acidification by Snx10

 描述（由申请人提供）：骨质疏松症的健康和经济影响继续使破骨细胞的骨吸收研究成为一个至关重要的研究重点。破骨细胞异常依赖于囊泡运输，这是骨吸收所必需的。因此，破坏（遗传或药理学）骨钙素囊泡运输废除再吸收活性。已知Snx家族的蛋白质介导内体分选、内吞作用、膜蛋白的再循环以及各种内体和高尔基体之间的运输。我们发现了Snx 10，一个在破骨细胞和胃中表达的家族成员，在胃中需要它来产生酸。我们通过基因捕获技术产生了Snx 10缺陷小鼠（Snx 10 ins/ins），并表征了骨表型。snx 10 ins/ins小鼠表现出一种复杂的表型，它是骨硬化症（由于破骨细胞吸收受损）和佝偻病（由于胃酸化受损和钙吸收不良导致矿化受损）的组合，称为骨硬化佝偻病。导致骨质疏松症的潜在机制目前尚不清楚。基于这些研究结果，我们得出结论，Snx 10是必不可少的体内骨稳态通过调节囊泡运输，因此在破骨细胞和胃的酸生产。在这项提案中，我们将使用细胞特异性Snx 10消融研究在骨骼和胃阐明的分子机制，Snx 10调节骨吸收和胃酸化骨稳态。这一提议具有很高的意义，因为它将表征一个新的候选基因，该基因参与人类骨骼疾病的发展，包括骨质疏松症和与缺钙相关的骨丢失。这些结果将改变骨硬化患者的治疗模式，这些患者的Snx 10和其他具有相似表达和活性模式的基因突变，其胃缺陷通常被忽视。更重要的是，我们的发现将显著地促进我们对控制破骨细胞功能的分子机制和胃肠道对骨稳态的控制的理解。

 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.