2. Academic Validation
  3. TRAF1 promotes osteoclastogenesis by enhancing metabolic adaptation to oxidative phosphorylation in an AKT-dependent manner

TRAF1 promotes osteoclastogenesis by enhancing metabolic adaptation to oxidative phosphorylation in an AKT-dependent manner

  • Mol Ther. 2025 Mar 5;33(3):933-949. doi: 10.1016/j.ymthe.2025.01.040.
Honglei Kang 1,  Renpeng Peng 2,  Yimin Dong 2,  Fuben Liao 3,  Meipeng Zhu 2,  Pengju Wang 2,  Shi-An Hu 2,  Peixuan Hu 2,  Jia Wang 4,  Zheming Liu 5,  Kehan Song 6,  Feng Li 7
Affiliations

Affiliations

  • 1 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.
  • 2 Department of Orthopaedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 3 Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China; Hubei Provincial Research Center for Precision Medicine of Cancer, Wuhan, China.
  • 4 Department of Orthopedics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
  • 5 Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China; Hubei Provincial Research Center for Precision Medicine of Cancer, Wuhan, China. Electronic address: zhemingliu@whu.edu.cn.
  • 6 Department of Orthopaedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Provincial Research Center for Precision Medicine of Cancer, Wuhan, China. Electronic address: kehansong@tjh.tjmu.edu.cn.
  • 7 Department of Orthopaedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: lifengmd@hust.edu.cn.
PMID: 39863932 DOI: 10.1016/j.ymthe.2025.01.040
Abstract

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.

Keywords

AKT; OXPHOS; TRAF1; osteoclast; osteoporosis.

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