IL-40 is up-regulated in the synovial fluid and cartilage of osteoarthritis patients and contributes to the alteration of chondrocytes phenotype in vitro

Abstract

Introduction IL-40 is a novel cytokine associated with autoimmune connective tissue disorders such as rheumatoid arthritis (RA) or Sjögren syndrome. We have previously shown an accumulation of IL-40 in the RA joint and its expression by immune cells and fibroblasts. Therefore, we aimed to assess the role of IL-40 in association with hyaline cartilage and chondrocyte activity. Methods Immunohistochemistry was employed to detect IL-40 in paired samples of loaded and unloaded regions of osteoarthritis (OA) cartilage ( n =5). Synovial fluid IL-40 was analysed by ELISA in OA ( n =31) and control individuals after knee injury ( n =34). The impact of IL-40 on chondrocytes was tested in vitro. Results IL-40 was found in chondrocytes of the superficial zone of the OA cartilage, both in loaded and unloaded explants. Additionally, only biopsies from loaded explants showed significant IL-40 positivity in transitional zone chondrocytes. Levels of IL-40 were significantly elevated in the synovial fluid from OA patients compared to controls ( p <0.0009) and correlated with synovial fluid leukocyte counts in OA (r=0.444, p =0.014). Chondrocytes exposed to IL-40 dose dependently increased in the secretion of pro-inflammatory cytokines IL-6 ( p <0.0001) and IL-8 ( p =0.004). Moreover, a dose dependent up-regulation of matrix degrading metalloproteinases MMP-1 ( p =0.004), MMP-3 ( p =0.031) and MMP-13 ( p =0.0002) upon IL-40 treatment was observed in contrast to untreated chondrocytes. Conclusion This study is the first to demonstrate the accumulation of IL-40 in OA cartilage and its up-regulation in the synovial fluid of OA patients compared to controls. In addition, extracellular IL-40 appears to play a role in promoting inflammation and cartilage destruction by driving chondrocyte behaviour towards a more aggressive phenotype. Supplementary Information The online version contains supplementary material available at 10.1186/s13075-024-03372-z.