SerpinA3N limits cartilage destruction in osteoarthritis by inhibiting macrophage-derived leucocyte elastase

Abstract

ObjectivesInflammatory 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.MethodsRNA 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-specificSerpina3n-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.ResultsRNA 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.ConclusionsSerpinA3N protects cartilage against catabolic factors produced by macrophages, including LE. SerpinA3N and LE represent new therapeutic targets to dampen cartilage damage in OA.