期刊
FRONTIERS IN IMMUNOLOGY
卷 12, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2021.676173
关键词
osteoarthritis; interleukin-17; cartilage; synovium; inflammation; transcriptomics; chondrocytes; synovial fibroblasts
类别
资金
- National Institute for Health Research Oxford Biomedical Research Centre
- Dunhill Foundation
- Royal College of Surgeons
- Lord Nuffield Trust
- Medical Research Council Career Development Fellowship [MR/V010182/1]
- Bone Cancer Research Trust
- Leducq Foundation
- Versus Arthritis Career Development Fellowship [22425]
- Wellcome Trust
- National Institute for Health Research
- Medical Research Council/UK Research and Innovation
- Versus Arthritis
Increased interleukin (IL)-17A has been identified in joints affected by osteoarthritis (OA), but the specific role of IL-17A and its family members IL-17AF and IL-17F in human OA pathophysiology remains unclear. Research findings suggest that IL-17 cytokines play a regulatory role in gene expression in chondrocytes and synovial fibroblasts, impacting pathways related to OA pathophysiology. IL-17A, IL-17AF, and IL-17F have shown varying levels of transcriptional response, with IL-17A being the strongest inducer, and the potential therapeutic use of anti-IL-17 treatment in OA patients with an inflammatory phenotype warrants further investigation.
Increased interleukin (IL)-17A has been identified in joints affected by osteoarthritis (OA), but it is unclear how IL-17A, and its family members IL-17AF and IL-17F, can contribute to human OA pathophysiology. Therefore, we aimed to evaluate the gene expression and signalling pathway activation effects of the different IL-17 family members in chondrocytes and synovial fibroblasts derived from cartilage and synovium of patients with end-stage knee OA. Immunohistochemistry staining confirmed that IL-17 receptor A (IL-17RA) and IL-17RC are expressed in end-stage OA-derived cartilage and synovium. Chondrocytes and synovial fibroblasts derived from end-stage OA patients were treated with IL-17A, IL-17AF, or IL-17F, and gene expression was assessed with bulk RNA-Seq. Hallmark pathway analysis showed that IL-17 cytokines regulated several OA pathophysiology-related pathways including immune-, angiogenesis-, and complement-pathways in both chondrocytes and synovial fibroblasts derived from end-stage OA patients. While overall IL-17A induced the strongest transcriptional response, followed by IL-17AF and IL-17F, not all genes followed this pattern. Disease-Gene Network analysis revealed that IL-17A-related changes in gene expression in these cells are associated with experimental arthritis, knee arthritis, and musculoskeletal disease gene-sets. Western blot analysis confirmed that IL-17A significantly activates p38 and p65 NF-kappa B. Incubation of chondrocytes and synovial fibroblasts with anti-IL-17A monoclonal antibody secukinumab significantly inhibited IL-17A-induced gene expression. In conclusion, the association of IL-17-induced transcriptional changes with arthritic gene-sets supports a role for IL-17A in OA pathophysiology. Future studies should further investigate the role of IL-17A in the OA joint to establish whether anti-IL-17 treatment could be a potential therapeutic option in OA patients with an inflammatory phenotype.
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