Department of Orthopedics, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
Taicang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Taicang, China.
Cell Death Dis. 2023 Sep 25;14(9):631. doi: 10.1038/s41419-023-06160-w.
Osteoporosis is not well treated due to the difficulty of finding commonalities between the various types of it. Iron homeostasis is a vital component in supporting biochemical functions, and iron overload is recognized as a common risk factor for osteoporosis. In this research, we found that there is indeed evidence of iron accumulation in the bone tissue of patients with osteoporosis and REPIN1, as an origin specific DNA binding protein, may play a key role in this process. We revealed that sh-Repin1 therapy can rescue bone loss in an iron-overload-induced osteoporosis mouse model. Knockdown of Repin1 can inhibit apoptosis and enhance the resistance of osteoblasts to iron overload toxicity. REPIN1 promoted apoptosis by regulating iron metabolism in osteoblasts. Mechanistically, knockdown of Repin1 decreased the expression of Lcn2, which ameliorated the toxic effects of intracellular iron overload. The anti-iron effect of lentivirus sh-Repin1 was partially reversed or replicated by changing LCN2 expression level via si-RNA or plasmid, which indirectly verified the key regulatory role of LCN2 as a downstream target. Furthermore, the levels of BCL2 and BAX, which play a key role in the mitochondrial apoptosis pathway, were affected. In summary, based on the results of clinical specimens, animal models and in vitro experiments, for the first time, we proved the key role of REPIN1 in iron metabolism-related osteoporosis.
由于难以找到各种类型骨质疏松症的共同点，因此骨质疏松症的治疗效果不佳。铁稳态是支持生化功能的重要组成部分，铁过载被认为是骨质疏松症的常见危险因素。在这项研究中，我们确实发现骨质疏松症患者的骨组织中有铁积累的证据，而作为一种起源特异性 DNA 结合蛋白的 REPIN1 可能在这个过程中发挥关键作用。我们揭示了 sh-Repin1 治疗可以挽救铁过载诱导的骨质疏松症小鼠模型中的骨丢失。Repin1 的敲低可以抑制成骨细胞的凋亡并增强其对铁过载毒性的抵抗力。REPIN1 通过调节成骨细胞中的铁代谢来促进细胞凋亡。在机制上，敲低 Repin1 会降低 Lcn2 的表达，从而减轻细胞内铁过载的毒性作用。通过 si-RNA 或质粒改变 LCN2 的表达水平，可部分逆转或复制慢病毒 sh-Repin1 的抗铁作用，间接验证了 LCN2 作为下游靶标发挥关键调节作用。此外，还影响了在线粒体凋亡途径中起关键作用的 BCL2 和 BAX 的水平。总之，基于临床标本、动物模型和体外实验的结果，我们首次证明了 REPIN1 在铁代谢相关骨质疏松症中的关键作用。
