The Key Laboratory of Aerospace Medicine, Ministry of Education, Air Force Medical University, Xi'an 710032, China.
State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing 100094, China.
Cells. 2022 Aug 19;11(16):2580. doi: 10.3390/cells11162580.
Bone loss caused by mechanical unloading is a threat to prolonged space flight and human health. Epigenetic modifications play a crucial role in varied biological processes, but the mechanism of histone modification on unloading-induced bone loss has rarely been studied. Here, we discovered for the first time that the methyltransferase Setdb1 was downregulated under the mechanical unloading both in vitro and in vivo so as to attenuate osteoblast proliferation. Furthermore, we found these interesting processes depended on the repression of Macrod2 expression triggered by Setdb1 catalyzing the formation of H3K9me3 in the promoter region. Mechanically, we revealed that Macrod2 was upregulated under mechanical unloading and suppressed osteoblast proliferation through the GSK-3β/β-catenin signaling pathway. Moreover, Atf7ip cooperatively contributed to osteoblast proliferation by changing the localization of Setdb1 under mechanical loading. In summary, this research elucidated the role of the Atf7ip/Setdb1/Macrod2 axis in osteoblast proliferation under mechanical unloading for the first time, which can be a potential protective strategy against unloading-induced bone loss.
机械负荷降低导致的骨质流失是对长期太空飞行和人类健康的威胁。表观遗传修饰在各种生物过程中起着至关重要的作用，但组蛋白修饰在负荷降低引起的骨质流失中的作用机制很少被研究。在这里，我们首次发现，甲基转移酶 Setdb1 在体外和体内的机械卸载下均下调，从而减弱成骨细胞的增殖。此外，我们发现这些有趣的过程依赖于 Setdb1 催化启动子区域 H3K9me3 形成所触发的 Macrod2 表达的抑制。在机械方面，我们揭示了 Macrod2 在机械卸载下上调，并通过 GSK-3β/β-catenin 信号通路抑制成骨细胞增殖。此外，Atf7ip 通过改变机械加载下 Setdb1 的定位共同促进成骨细胞增殖。总之，本研究首次阐明了 Atf7ip/Setdb1/Macrod2 轴在机械卸载下成骨细胞增殖中的作用，这可能是对抗负荷降低引起的骨质流失的一种潜在保护策略。
