1. The CD163/TWEAK/Fn14 axis: A potential therapeutic target for alleviating inflammatory bone loss
- Author
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Ji-kun Qian, Yuan Ma, Xuan Huang, Xiao-ran Li, Ya-fei Xu, Zi-ying Liu, Yuan Gu, Ke Shen, Liang-jie Tian, Yu-tian Wang, Ning-ning Cheng, Bing-sheng Yang, Kui-yuan Huang, Yu Chai, Guan-qiao Liu, Nai-qian Cui, Song-yun Deng, Nan Jiang, Dao-rong Xu, and Bin Yu
- Subjects
Bone homeostasis ,CD163 ,Inflammation ,Osteoporosis ,Osteoclast ,TWEAK ,Diseases of the musculoskeletal system ,RC925-935 - Abstract
Objective: Osteoclast (OC) over-activation is an important cause of bone loss that is strongly correlated with inflammation. Although the CD163/TWEAK/Fn14 axis has been implicated in several inflammatory pathologies, its contributions to inflammatory bone loss remain poorly understood. This study aimed to evaluate the interaction of the CD163/TWEAK/Fn14 axis with OC in inflammatory bone loss. Methods: To assess the role of CD163 in bone homeostasis, we characterized the bone phenotypes of CD163-deficient mice and their wild-type littermates. CD163 and TWEAK levels were evaluated in the bone marrow of mice with LPS-induced bone loss and individuals with rheumatoid arthritis (RA). Bone mass changes were assessed using uCT and histology following supplementation with recombinant mouse CD163 protein (rCD163) or blockade of TWEAK/Fn14 signaling in CD163-deficient mice and mice with LPS-induced bone loss. The impact of CD163/TWEAK on OC differentiation and bone resorption capacity was analyzed in vitro. Results: CD163 deficiency caused decreased bone mass and increased OC abundance. Lower CD163 expression and higher TWEAK expression were observed in the bone marrow of mice with LPS-induced bone loss and individuals with RA. TWEAK, mainly derived from CD68+ macrophages, was responsible for bone loss, and supplementing rCD163 or blocking TWEAK/Fn14 signaling contributed to rescue bone loss. TWEAK/Fn14 synergistically promoted RANKL-dependent OC differentiation and bone resorption capability through downstream mitogen-activated protein kinases (MAPK) signaling, while the pro-osteoclastic effect of TWEAK was suppressed by CD163. Conclusion: Our findings suggest that the CD163/TWEAK/Fn14 axis is a potential therapeutic target for inflammatory bone loss by regulating osteoclastogenesis.
- Published
- 2024
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