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Abstract
Objectives Inflammatory mediators such as interleukin 6 (IL-6) are known to activate catabolic responses in chondrocytes during osteoarthritis (OA). This study aimed to investigate the role of a downstream target gene of IL-6, the serine protease inhibitor SerpinA3N, in the development of cartilage damage in OA.
Methods RNA sequencing was performed in murine primary chondrocytes treated with IL-6, and identified target genes were confirmed in human and murine OA cartilage samples. Male cartilage-specific Serpina3n-deficient mice and control mice underwent meniscectomy (MNX) or sham surgery at 10 weeks of age. Intra-articular injections of SerpinA3N or sivelestat (an inhibitor of leucocyte elastase (LE), a substrate for SerpinA3N) were performed in wild-type mice after MNX. Joint damage was assessed 3–9 weeks after surgery by histology and micro-CT. The effect of sivelestat was assessed in cartilage explants exposed to macrophage-derived conditioned media.
Results RNA sequencing revealed that SerpinA3N is a major target gene of IL-6 in chondrocytes. The expression of SerpinA3N is increased in OA cartilage. Conditional loss of SerpinA3N in chondrocytes aggravated OA in mice, while intra-articular injection of SerpinA3N limited joint damage. Chondrocytes did not produce serine proteases targeted by SerpinA3N. By contrast, macrophages produced LE on IL-6 stimulation. Sivelestat limited the cartilage catabolism induced by conditioned media derived from IL-6-stimulated macrophages. Additionally, an intra-articular injection of sivelestat is protected against OA in the MNX model.
Conclusions SerpinA3N protects cartilage against catabolic factors produced by macrophages, including LE. SerpinA3N and LE represent new therapeutic targets to dampen cartilage damage in OA.
- Chondrocytes
- Osteoarthritis
- Inflammation
Data availability statement
Data are available in a public, open access repository. Data are available upon reasonable request. RNA sequencing data that support the findings of this study have been deposited in GEO (accession number GSE271151). Other data are available upon reasonable request.
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Data availability statement
Data are available in a public, open access repository. Data are available upon reasonable request. RNA sequencing data that support the findings of this study have been deposited in GEO (accession number GSE271151). Other data are available upon reasonable request.
Footnotes
Handling editor Josef S Smolen
X @A_Latourte
Contributors AL, MC-S, EH and PR conceived the study and designed the experiments. AL, SJ, AC, CC, YJ, TG, JD and H-KE were involved in acquisition and analysis of data. AL, TG, H-KE, MC-S, EH and PR interpreted data. AL drafted the manuscript and all authors critically revised it and gave their final approval for publication. All authors agree to be accountable for all aspects of the work, and to ensure that there are no questions regarding the accuracy or integrity of any part of the work. AL is responsible for the overall content as guarantor. He accepts full responsibility for the finished work and the conduct of the study, had access to the data and controlled the decision to publish
Funding The sequencing facility of the Institut Jacques Monod, Paris, was supported by grants from the University Paris Cité, the Fondation pour la Recherche Médicale (DGE20111123014), and the Région Ile-de-France (11015901)
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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