Interleukin-17A Causes Osteoarthritis-Like Transcriptional Changes in Human Osteoarthritis-Derived Chondrocytes and Synovial Fibroblasts In Vitro

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.

Unraveling the Signaling Secretome of Platelet-Rich Plasma: Towards a Better Understanding of Its Therapeutic Potential in Knee Osteoarthritis

“…Interestingly, predictions showed that PRP molecules modulate IL-17 signaling. Recent data support a role for IL-17A in OA joints [45] and set the grounds to investigate this specific inflammatory phenotype. IL-17 in increased in obese and associated to obesity-related inflammatory comorbidities [46].…”

Increased Chondroprotective Effect of Combining Hyaluronic Acid with a Glucocorticoid Compared to Separate Administration on Cytokine-Treated Osteoarthritic Chondrocytes in a 2D Culture

“…The pro-inflammatory cytokine IL-1β is one of the central pro-inflammatory cytokines in many diseases and activates various pathways leading to the progression of osteoarthritis [24,25]. IL-17, on the other hand, is crucially involved in changes to the transcriptome of chondrocytes, which has also been shown in studies of osteoarthritis patients [26,27]. In addition, IL-17 leads to an increase in TNF-α production [28], which is shown in our study within the group of simple cytokine treatments.…”

Autologous Protein Solution processing alters lymphoid and myeloid cell populations and modulates gene expression dependent on cell type

“…S 7 a). IL-17 cytokines have demonstrated pathophysiology in osteoarthritis in preclinical and clinical studies [ 25 ]. Quantification of Il17f mRNA in the draining inguinal lymph node increased in some mice in the saline and APS without cell treatment groups compared to the other groups, although did not reach statistical significance (Fig.…”