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
  • 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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