Objective Increasing evidence suggests that impaired cartilage is a substantial risk factor for the progression from hyperuricaemia to gout. Since the relationship between cartilage matrix protein and gout flares remains unclear, we investigated its role in monosodium urate (MSU) crystallisation and following inflammation.
Methods Briefly, we screened for cartilage matrix in synovial fluid from gouty arthritis patients with cartilage injuries. After identifying a correlation between crystals and matrix molecules, we conducted image analysis and classification of crystal phenotypes according to their morphology. We then evaluated the differences between the cartilage matrix protein-MSU complex and the pure MSU crystal in their interaction with immune cells and identified the related signalling pathway.
Results Type II collagen (CII) was found to be enriched around MSU crystals in synovial fluid after cartilage injury. Imaging analysis revealed that CII regulated the morphology of single crystals and the alignment of crystal bows in the co-crystalline system, leading to greater phagocytosis and oxidative stress in macrophages. Furthermore, CII upregulated MSU-induced chemokine and proinflammatory cytokine expression in macrophages, thereby promoting the recruitment of leucocytes. Mechanistically, CII enhanced MSU-mediated inflammation by activating the integrin β1(ITGB1)-dependent TLR2/4-NF-κB signal pathway.
Conclusion Our study demonstrates that the release of CII and protein-crystal adsorption modifies the crystal profile and promotes the early immune response in MSU-mediated inflammation. These findings open up a new path for understanding the relationship between cartilage injuries and the early immune response in gout flares.
- crystal arthropathies
Data availability statement
Data are available on reasonable request.
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HX and BZ contributed equally.
Correction notice This article has been corrected since it published Online First. The author details for MinBiao Ji have been updated.
Contributors YH is responsible for the overall content as guarantor. YH, MJ and RH designed and directed the study. HX, BZ, WW, ZC and LC performed molecular biology and optical experiments. BZ and YC performed stimulated Raman scattering microscopy experiments and data collection. FZ and JS performed programming and image analysis. XZ, YX and JC carried out the design of the experimentals and analysis of the results. RH, MJ, HX and BZ wrote the manuscript with contributions from all the authors.
Funding This work was supported by the National Key R&D Programme of China (grant numbers 2020YFA0803800, 2021YFF0502900); National Natural Science Foundation of China (61975033, 32170899); and Shanghai Municipal Science and Technology Major Project No. 2018SHZDZX01 and ZJLab.
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
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