Kang Honglei, Peng Renpeng, Dong Yimin, Liao Fuben, Zhu Meipeng, Wang Pengju, Hu Shi-An, Hu Peixuan, Wang Jia, Liu Zheming, Song Kehan, Li Feng
Department of Orthopaedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Research Institute of Shenzhen Huazhong University of Science and Technology, Shen Zhen, China.
Department of Orthopaedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Mol Ther. 2025 Mar 5;33(3):933-949. doi: 10.1016/j.ymthe.2025.01.040. Epub 2025 Jan 25.
Tumor necrosis factor receptor-associated factor 1 (TRAF1) is a crucial signaling adaptor involved in multiple cellular events. However, its role in regulating osteoclastogenesis and energy metabolism remains unclear. Here, we report that TRAF1 promotes osteoclastogenesis and oxidative phosphorylation (OXPHOS). Employing RNA sequencing, we found that TRAF1 is markedly upregulated during osteoclastogenesis and is positively associated with osteoporosis. TRAF1 knockout inhibits osteoclastogenesis and increases bone mass in both normal and ovariectomized adult mice without affecting bone mass in childhood. Furthermore, TRAF1 promotes osteoclast OXPHOS by increasing the phosphorylation level of AKT. Mechanistically, TRAF1 functions to inhibit TRAF2-induced ubiquitination of Gβl, a known activator of AKT, and further upregulates AKT phosphorylation. Rescue experiments revealed that the inhibitory effects of TRAF1 knockout on osteoclastogenesis, OXPHOS, and bone mass are dependent on AKT. Collectively, our findings uncover a previously unrecognized function of TRAF1 in regulating osteoclastogenesis and energy metabolism, and establish a novel TRAF1-AKT-OXPHOS axis in osteoclasts.
肿瘤坏死因子受体相关因子1（TRAF1）是一种参与多种细胞事件的关键信号衔接蛋白。然而，其在调节破骨细胞生成和能量代谢中的作用仍不清楚。在此，我们报告TRAF1促进破骨细胞生成和氧化磷酸化（OXPHOS）。通过RNA测序，我们发现TRAF1在破骨细胞生成过程中显著上调，且与骨质疏松症呈正相关。TRAF1基因敲除抑制正常和去卵巢成年小鼠的破骨细胞生成并增加骨量，而不影响幼年小鼠的骨量。此外，TRAF1通过增加AKT的磷酸化水平促进破骨细胞的氧化磷酸化。机制上，TRAF1的作用是抑制TRAF2诱导的Gβl（一种已知的AKT激活剂）的泛素化，并进一步上调AKT磷酸化。拯救实验表明，TRAF1基因敲除对破骨细胞生成、氧化磷酸化和骨量的抑制作用依赖于AKT。总的来说，我们的研究结果揭示了TRAF1在调节破骨细胞生成和能量代谢方面以前未被认识的功能，并在破骨细胞中建立了一种新的TRAF1-AKT-氧化磷酸化轴。
