Guo Zengfeng, Hu Yawei, Zhou Jianhua, Zhang Yandong, Zhang Junde, Yang Linbo, Wang Shenghang, Wu Jiawen, Yang Jiancheng
Department of Spine Surgery, People's Hospital of Longhua, Shenzhen, 518109, Guangdong, China; Guangzhou University of Chinese Medicine, Guangzhou, 510006, Guangdong, China.
Department of Spine Surgery, People's Hospital of Longhua, Shenzhen, 518109, Guangdong, China.
Biochem Biophys Res Commun. 2025 Jan;743:151152. doi: 10.1016/j.bbrc.2024.151152. Epub 2024 Dec 6.
Iron overload leads to apoptosis and increased expression of receptor activator of nuclear factor kappa-Β ligand (RANKL) in osteocytes, which in turn accelerates osteoclastogenesis. Since osteocytes are the main RANKL producers, we hypothesized that apoptotic osteocytes increase RANKL expression in osteocytes, which in turn stimulates osteoclastogenesis and bone resorption. In this study, alendronate or IG9402, a bisphosphonate (BP) analog which does not inhibit bone resorption, inhibited iron overload-induced osteocyte apoptosis and increased RANKL expression. Both BPs also prevented osteoblast apoptosis but did not inhibit the increase in osteoblastic RANKL. Alendronate, but not IG9402, prevented the increase in osteoclastogenesis and serum levels of the bone resorption marker C-telopeptide of type I collagen (CTX) in iron-overloaded mice. Alendronate also prevented the iron overload-induced reduction in femoral bone mineral density, disruption of bone microstructure, and weakness of bone strength. Although IG9402 did not prevent bone loss due to iron overload, it partially prevented reduction of strength, suggesting that osteocyte viability contributes to the maintenance of bone strength. In conclusion, although osteocyte apoptosis in the presence of iron overload leads to an increase in osteocytic RANKL production. However, blocking these events was not sufficient to inhibit iron overload-induced osteoclastogenesis and bone loss.
铁过载导致骨细胞凋亡，并增加核因子κB受体激活剂配体（RANKL）的表达，进而加速破骨细胞生成。由于骨细胞是RANKL的主要产生者，我们推测凋亡的骨细胞会增加骨细胞中RANKL的表达，进而刺激破骨细胞生成和骨吸收。在本研究中，阿仑膦酸盐或IG9402（一种不抑制骨吸收的双膦酸盐（BP）类似物）可抑制铁过载诱导的骨细胞凋亡并增加RANKL表达。两种BP还可预防成骨细胞凋亡，但不抑制成骨细胞RANKL的增加。阿仑膦酸盐而非IG9402可预防铁过载小鼠破骨细胞生成增加以及骨吸收标志物I型胶原C末端肽（CTX）血清水平升高。阿仑膦酸盐还可预防铁过载诱导的股骨骨矿物质密度降低、骨微结构破坏和骨强度减弱。虽然IG9402不能预防铁过载导致的骨质流失，但它部分预防了强度降低，表明骨细胞活力有助于维持骨强度。总之，虽然铁过载时骨细胞凋亡会导致骨细胞RANKL产生增加。然而，阻断这些事件不足以抑制铁过载诱导的破骨细胞生成和骨质流失。
