骨细胞内质网SERCA钙泵功能损伤在2型糖尿病骨骼应力敏感性降低中的作用及机制研究

T2DM患者存在骨质量和力敏感性降低的问题，导致骨脆性和骨折风险增加。但T2DM骨骼力敏感性受损机制是什么，相比正常骨骼转导应力途径有何差异，迄今尚不明确。骨细胞被证实是骨中核心的力感受器，我们首次发现骨骼通过骨细胞多尖峰钙振荡响应外界应力。研究报道心血管细胞内质网SERCA钙泵对高糖环境具有高敏感性，SERCA损伤被认为是糖尿病心血管并发症重要诱因。我们预实验发现糖尿病骨细胞表现出钙瞬变衰减时间延长和幅值降低等可能与SERCA损伤相关的钙信号特征，故本项目提出骨细胞SERCA损伤介导T2DM骨应力敏感性衰退新思路，拟阐明①T2DM对骨细胞SERCA的损伤效应及与钙信号的相关性；②SERCA损伤对T2DM骨细胞力学信号转导的影响；③上调骨细胞SERCA是否显著提升T2DM骨骼力敏感性。本项目有望进一步丰富对T2DM骨力学信号转导和骨衰退机制的认识，并为抗T2DM骨衰退新药研发提供重要参考。

Patients with type 2 diabetes mellitus (T2DM) have the issues of the reductions of bone quality and bone mechanosensitivity, leading to the significant increase of bone fragility and bone fracture risks. However, the mechanisms of decreased bone mechanosensitivity and the potential difference in signaling pathways for the T2DM skeleton transducing external mechanical stimulation as compared with the normal skeleton, remain unclear thus far. It is well substantiated that osteocytes act as the key mechanosensors in bone. Moreover, our studies have shown that the skeleton responses and processes external mechanical signals via the unique calcium oscillations with multiple robust calcium spikes. Substantial studies have reported that Ca2+-ATPase (SERCA) in endoplasmic reticulum of cardiovascular cells is highly sensitive to the high glucose environment, and the SERCA impairment is considered to be a critical factor contributing to T2DM-associated cardiovascular complications. Our preliminary experiment has also shown that osteocytes exhibited prolonged spike relaxation time and decreased spike magnitude of calcium transients in response to mechanical stimulation, which may be potentially associated with decreased SERCA activity. Thus, the current study proposes that the impairment of SERCA in osteocytes mediates the deterioration of bone mechanosensitivity in T2DM skeleton. This study aims to investigate the following three aspects: (1) the impairment of SERCA in osteocytes induced by T2DM and its correlation with osteocyte calcium signaling; (2) the effects of the SERCA impairment on osteocyte mechanotransduction in T2DM skeleton; (3) whether up-regulation of SERCA can significantly increase T2DM bone mechanosensitivity. This study not only enriches our understanding of the mechanisms of T2DM bone mechanotransduction and bone deterioration, but also provides important experimental evidence for new drug development for resisting T2DM-associated bone deterioration.