Department of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518033, P. R. China.
Department of Orthopedics Surgery, Suzhou Municipal Hospital/The Affiliated Suzhou Hospital of Nanjing Medical University, Gusu School, Nanjing Medical University, Suzhou, China.
Cell Mol Life Sci. 2024 Aug 19;81(1):360. doi: 10.1007/s00018-024-05376-z.
Iron deficiency is a prevalent nutritional deficit associated with organ damage and dysfunction. Recent research increasingly associates iron deficiency with bone metabolism dysfunction, although the precise underlying mechanisms remain unclear. Some studies have proposed that iron-dependent methylation-erasing enzyme activity regulates cell proliferation and differentiation under physiological or pathological conditions. However, it remains uncertain whether iron deficiency inhibits the activation of quiescent mesenchymal stem cells (MSCs) by affecting histone demethylase activity. In our study, we identified KDM4D as a key player in the activation of quiescent MSCs. Under conditions of iron deficiency, the H3K9me3 demethylase activity of KDM4D significantly decreased. This alteration resulted in increased heterochromatin with H3K9me3 near the PIK3R3 promoter, suppressing PIK3R3 expression and subsequently inhibiting the activation of quiescent MSCs via the PI3K-Akt-Foxo1 pathway. Iron-deficient mice displayed significantly impaired bone marrow MSCs activation and decreased bone mass compared to normal mice. Modulating the PI3K-Akt-Foxo1 pathway could reverse iron deficiency-induced bone loss.
缺铁是一种普遍存在的营养缺乏症，与器官损伤和功能障碍有关。最近的研究越来越多地将缺铁与骨代谢功能障碍联系起来，尽管确切的潜在机制仍不清楚。一些研究提出，铁依赖性甲基化擦除酶活性在生理或病理条件下调节细胞增殖和分化。然而，目前尚不确定缺铁是否通过影响组蛋白去甲基化酶活性来抑制静息间充质干细胞（MSCs）的激活。在我们的研究中，我们确定 KDM4D 是静息 MSCs 激活的关键因子。在缺铁条件下，KDM4D 的 H3K9me3 去甲基化酶活性显著降低。这种改变导致靠近 PIK3R3 启动子的 H3K9me3 异染色质增加，抑制 PIK3R3 表达，进而通过 PI3K-Akt-Foxo1 通路抑制静息 MSCs 的激活。与正常小鼠相比，缺铁小鼠的骨髓间充质干细胞激活明显受损，骨量减少。调节 PI3K-Akt-Foxo1 通路可以逆转缺铁引起的骨丢失。
