Abstract
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-κB. 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.
Highlights
Osteoarthritis (OA) is the most common musculoskeletal disease, affecting 8.75 million people in the UK alone
This study aimed to identify and compare the changes in gene expression and activation of intracellular signalling pathways induced by IL-17A, IL-17F, and IL-17AF in chondrocytes and synovial fibroblasts derived from patients with end-stage knee OA
Cartilage and synovium from end-stage OA patients undergoing total knee replacement surgery were either formalin-fixed or digested to isolate and expand resident fibroblasts. To validate that these fibroblasts can respond to IL-17 cytokines, mRNA expression of their receptors IL17RA and IL17RC was assessed by Real-time quantitative polymerase chain reaction (RT-qPCR) (Figure 1A)
Summary
Osteoarthritis (OA) is the most common musculoskeletal disease, affecting 8.75 million people in the UK alone. Six phenotypes of OA have been proposed by Dell’Isola et al, including the chronic pain phenotype, inflammatory phenotype, metabolic syndrome phenotype, bone and cartilage metabolism phenotype, mechanical overload phenotype, and minimal joint disease phenotype [10]. These clinical phenotypes and endotypes can help to stratify disease, and help to define meaningful end points; their incorporation throughout the translational pipeline is critical to identify much-needed disease modifying treatments for OA [8]. Because there are several proinflammatory mediators that are thought to be involved in OA pathogenesis, including interleukin (IL)-1b, TNF-a, IL-6, and IL-17 [5, 11], the inflammatory phenotype could be well-suited to therapeutic antibodies that target these proinflammatory pathways [9, 12]
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