Research Paper Volume 13, Issue 4 pp 5804—5823

Macrophage migration inhibitory factor activates the inflammatory response in joint capsule fibroblasts following post-traumatic joint contracture

Yuxin Zhang1,2, *, , Shenji Lu1, *, , Shuai Fan1, , Lili Xu1, , Xin Jiang1, , Kexin Wang3, , Bin Cai1, ,

  • 1 Department of Rehabilitation Medicine, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
  • 2 Shanghai Key Laboratory of Orthopedic Implants, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
  • 3 School of Kinesiology, Shanghai University of Sport, Shanghai 200438, China
* Equal contribution

Received: September 11, 2020       Accepted: November 23, 2020       Published: February 17, 2021
How to Cite

Copyright: © 2021 Zhang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Objectives: Joint capsule fibrosis caused by excessive inflammation leading to post-traumatic joint contracture (PTJC). Fibroblasts trigger inflammation under the challenge of various proinflammatory cytokines. Macrophage migration inhibitory factor (MIF) is a prominent proinflammatory cytokine involved in inflammation- and fibrosis-associated pathophysiology, we investigated the role of MIF in PTJC.

Methods: Using rat PTJC model and fibroblast inflammation model, we detected MIF expression in posterior joint capsule. Primary joint capsule fibroblasts (JFs) were used to investigate the effects of MIF on cell proliferation, migration and proinflammatory cytokines production. The mechanism of JF-mediated events was evaluated by qRT-PCR, western blot and immunoprecipitation. We screened the mRNA expression profile to identify gene candidates that mediate the effect of MIF on JFs.

Results: MIF increased in posterior joint capsule following PTJC and co-localized with fibroblasts. Injection of MIF inhibitor significantly suppressed joint capsule inflammation and fibrosis. In vitro, MIF promoted JF proliferation, migration, and inflammation by regulating mitogen-activated protein kinase/nuclear factor-κB pathway through coupling with CD74. Transcriptome analysis revealed that lipid metabolism-related factors Pla2g2a, Angptl4, and Sgpp2, downstream of MIF/CD74, were potentially implicated in JF inflammation.

Conclusion: MIF/CD74 axis elicited JF inflammation and may provide new therapeutic targets for joint capsule fibrosis in PTJC.


COX2: cyclooxygenases2; DMSO: dimethylsulphoxide; ERK: extracellular regulated protein kinases; GAPDH: glyceraldehyde 3-phosphate dehydrogenase; IFN-γ: interferon-γ; JNK: c-Jun N-terminal kinase; LPS: lipopolysaccharide; MCP-1: monocyte chemotactic protein-1; PBS: phosphate-buffered saline.