2. Academic Validation
  3. The CD163/TWEAK/Fn14 axis: A potential therapeutic target for alleviating inflammatory bone loss

The CD163/TWEAK/Fn14 axis: A potential therapeutic target for alleviating inflammatory bone loss

  • J Orthop Translat. 2024 Oct 4:49:82-95. doi: 10.1016/j.jot.2024.09.002.
Ji-Kun Qian 1 2,  Yuan Ma 2,  Xuan Huang 3,  Xiao-Ran Li 3,  Ya-Fei Xu 1,  Zi-Ying Liu 3,  Yuan Gu 2,  Ke Shen 2,  Liang-Jie Tian 2,  Yu-Tian Wang 2,  Ning-Ning Cheng 4,  Bing-Sheng Yang 2,  Kui-Yuan Huang 5,  Yu Chai 2,  Guan-Qiao Liu 2,  Nai-Qian Cui 2,  Song-Yun Deng 6,  Nan Jiang 2,  Dao-Rong Xu 2,  Bin Yu 2
Affiliations

Affiliations

  • 1 Division of Orthopaedics and Traumatology, Department of Orthopaedics, The Seventh Affiliated Hospital, Southern Medical University, Foshan, 528200, China.
  • 2 Division of Orthopaedics and Traumatology, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
  • 3 Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
  • 4 Department of Obstetrics, The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China.
  • 5 Department of Gastroenterology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330000, China.
  • 6 Department of Orthopaedics and Traumatology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China.
PMID: 39430128 DOI: 10.1016/j.jot.2024.09.002
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.

Keywords

Bone homeostasis; CD163; Inflammation; Osteoclast; Osteoporosis; TWEAK.

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