m6A甲基化酶METTL3在FSH促进绝经后骨质疏松发生中的作用及其机制研究

The incidence of osteoporosis in postmenopausal women has increased significantly. Abnormal proliferation of osteoclast (OC) is the key link. FSH can promote OC proliferation, but its mechanism has not been elucidated. Recent studies have shown that m6A methylation can regulate the occurrence of osteoporosis. Our preliminary study found that FSH up-regulated the expression of methylase METTL3 in OC, and the role in promoting OC proliferation by FSH was significantly inhibited after silencing METTL3. Further screening revealed that TRAP, the OC activity marker protein, was the target gene of METTL3. Therefore, the scientific questions were raised: FSH up-regulated the expression of METTL3 to regulate TRAP, and promoted OC proliferation and osteoporosis. This project intends to clarify the regulation of METTL3 by FSH and its signaling mechanism, namely the role of PI3K/Akt pathway; explore the methylation regulation effect of METTL3 on TRAP, confirm its role in promoting OC proliferation by FSH; verify the role of METTL3/TRAP in promoting osteoporosis of FSH by gene knockout mice and clinical samples, and analyze its correlation. This project will reveal for the first time the new mechanism of FSH promoting the occurrence of osteoporosis through m6A pathway, and hopefully provide a new target for the intervention and treatment of postmenopausal osteoporosis.

女性在绝经后骨质疏松发病率明显上升，破骨细胞(Osteoclast,OC)增殖异常是其关键环节。FSH可促进OC增殖，但其机制不清。最新研究表明：m6A甲基化可调控骨质疏松发生。预实验显示：FSH上调OC甲基化酶METTL3表达；沉默METTL3后，FSH促OC增殖效应受到明显抑制。进一步筛选发现：OC活性标志蛋白TRAP为METTL3的靶基因。由此提出科学问题：FSH上调METTL3调控TRAP表达，促进OC增殖和骨质疏松发生。本项目拟明确FSH对METTL3的调控及其信号机制，即PI3K/Akt通路的作用；探讨METTL3对TRAP的甲基化调控效应，确认其在FSH促OC增殖中的作用；利用基因敲除小鼠和临床样本，验证METTL3/TRAP在FSH促骨质疏松中的作用，分析其相关性。本项目将首次揭示FSH通过m6A途径促进骨质疏松发生的新机制，有望为绝经后骨质疏松的干预治疗提供新靶点。

女性在绝经后骨质疏松发病率明显上升，破骨细胞(Osteoclast, OC)增殖和侵袭异常是其关键环节。FSH可促进破骨细胞增殖，但其机制不清。近年的研究表明：m6A甲基化可调控骨质疏松发生。我们在细胞实验上证实：FSH可通过上调破骨细胞甲基化酶METTL3表达，促进破骨细胞的增殖和侵袭效应；明确FSH对METTL3的调控及其信号机制，即FSH通过PI3K/Akt通路上调METTL3；并进一步筛选发现：破骨细胞功能相关蛋白CTSK为METTL3的下游基因，我们明确了FSH对CTSK的调控，确认了METTL3在FSH调控CTSK表达中的作用。整体动物水平上，我们在构建的破骨细胞特异性敲除METTL3的雌鼠模型上，利用去势手术（卵巢切除术）造成小鼠骨质疏松，并给予小鼠FSH，通过影像学检测和组织形态学分析，验证了METTL3在FSH促骨质疏松中的作用。本项目首次揭示FSH通过m6A途径促进骨质疏松发生的新机制，为绝经后骨质疏松的干预治疗提供新靶点。