The objective of this study was to develop a serum biochemical marker of the degradation of type III and IV collagens, as an index of synovium turnover, and evaluate its performance in patients with rheumatoid arthritis (RA). An enzyme-linked immunosorbent assay for serum synovial collagen fragments (Col3-4) was developed using an antibody recognizing a specific sequence from human type III collagen, which shares 70% homology with type IV collagen. Immunohistochemistry was performed to localize Col3-4 and the matrix metalloprotease MMP-9 which is upregulated in RA synovial fibroblasts in the synovial tissue from a RA patient. Serum Col3-4 was measured in patients with RA (n = 66, 73% women, mean age 62 years, median disease activity score 28 with erythrocyte sedimentation rate (DAS28-ESR) 2.6) and in sex and age matched healthy controls (n = 70, 76% women, mean age 59 years). Col3-4 immunoassay demonstrated adequate analytical performances and recognized a circulating neoepitope resulting from the cleavage of type III and IV collagens. In RA synovium tissue, Col3-4 fragments were localized in the lining layer where destructive fibroblasts are present and around blood vessels rich in type IV collagen. MMP-9 colocalized with Col3-4 staining and efficiently released Col3-4 fragments from type III and type IV collagen digestion. Serum Col3-4 was markedly increased in patients with RA (+240% vs controls, p < 0.0001) and correlated with DAS28-ESR (r = 0.53, p < 0.0001). Patients with RA and active disease (DAS28-ESR > 3.2, n = 20) had 896% (p < 0.0001) higher levels than subjects with low activity (n = 46). Serum Col3-4 is a specific and sensitive biochemical marker reflecting MMP- mediated type III and IV collagen degradation from synovial tissue. Serum Col3-4 levels are markedly increased in patients with RA, particularly in those with active disease, suggesting that it may be useful for the clinical investigation of RA.
Copyright: © 2023 Gineyts et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.