Osteoporosis (OP) is a common skeletal disease involving low bone mineral density (BMD) that often leads to fragility fracture, and its development is affected by multiple cellular pathologies and associated with marked epigenetic alterations of osteogenic genes. Proper physical exercise is beneficial for bone health and OP and reportedly possesses epigenetic modulating capacities; however, whether the protective effects of exercise on OP involve epigenetic mechanisms is unclear. Here, we report that epigenetic derepression of nuclear factor erythroid derived 2-related factor-2 (Nrf2), a master regulator of oxidative stress critically involved in the pathogenesis of OP, mediates the significant osteoprotective effects of running exercise (RE) in a mouse model of OP induced by ovariectomy. We showed that Nrf2 gene knockout (Nfe2l2^−/−) ovariectomized mice displayed a worse BMD reduction than the controls, identifying Nrf2 as a critical antiosteoporotic factor. Further, femoral Nrf2 was markedly repressed with concomitant DNA methyltransferase (Dnmt) 1/Dnmt3a/Dnmt3b elevations and Nrf2 promoter hypermethylation in both patients with OP and ovariectomized mice. However, daily 1-h treadmill RE significantly corrected epigenetic alterations, recovered Nrf2 loss and improved the femur bone mass and trabecular microstructure. Consistently, RE also normalized the adverse expression of major osteogenic factors, including osteoblast/osteoclast markers, Nrf2 downstream antioxidant enzymes and proinflammatory cytokines. More importantly, the RE-conferred osteoprotective effects observed in the wild-type control mice were largely abolished in the Nfe2l2^−/− mice. Thus, Nrf2 repression due to aberrant Dnmt elevation and subsequent Nrf2 promoter hypermethylation is likely an important epigenetic feature of the pathogenesis of OP, and Nrf2 derepression is essential for the antiosteoporotic effects of RE.

骨质疏松症（OP）是一种常见的骨骼疾病，涉及低骨矿物质密度（BMD），通常会导致脆性骨折，其发展受到多种细胞病理学的影响，并与成骨基因的显性表观遗传改变有关。适当的体育锻炼有益于骨骼健康和骨质疏松症，据报道具有表观遗传调控能力。然而，运动对OP的保护作用是否涉及表观遗传机制尚不清楚。在这里，我们报告说，核因子红系衍生的2相关因子2（Nrf2），氧化应激的主要调节因子，主要参与OP的发病机理的表观遗传抑制，在小鼠中进行跑步运动（RE）的重要骨保护作用。卵巢切除术诱发的OP模型。我们证明了Nrf2基因敲除（Nfe2l2^-/-）切除卵巢的小鼠的BMD降低比对照组更严重，从而确定Nrf2是关键的抗骨质疏松因子。此外，OP和去卵巢小鼠均伴有DNA甲基转移酶（Dnmt）1 / Dnmt3a / Dnmt3b升高和Nrf2启动子过度甲基化，显着抑制了股骨Nrf2。但是，每天1小时的跑步机RE可以显着纠正表观遗传学改变，恢复Nrf2损失并改善股骨质量和小梁微结构。始终如一，RE还使主要成骨因子的不良表达正常化，包括成骨细胞/破骨细胞标记，Nrf2下游抗氧化酶和促炎细胞因子。更重要的是，在Nfe2l2中，野生型对照小鼠中观察到的RE赋予的骨保护作用已被基本消除。^{-/ -}小鼠。因此，由于异常的Dnmt升高引起的Nrf2抑制以及随后的Nrf2启动子过度甲基化可能是OP发病机理的重要表观遗传学特征，而Nrf2的抑制对于RE的抗骨质疏松作用至关重要。