Inserm UMR-S 1132, Université Paris Cité, Paris, France
Rheumatology Department, Hôpital Lariboisière APHP.Nord, Paris, France.
Ann Rheum Dis. 2024 Nov 14;83(12):1781-1790. doi: 10.1136/ard-2024-225645.
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.
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 -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.
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.
SerpinA3N protects cartilage against catabolic factors produced by macrophages, including LE. SerpinA3N and LE represent new therapeutic targets to dampen cartilage damage in OA.
已知白细胞介素 6（IL-6）等炎症介质可在骨关节炎（OA）期间激活软骨细胞的分解代谢反应。本研究旨在探讨 IL-6 的下游靶基因丝氨酸蛋白酶抑制剂 SerpinA3N 在 OA 软骨损伤发展中的作用。
对用 IL-6 处理的鼠原代软骨细胞进行 RNA 测序，并在人及鼠 OA 软骨样本中验证了鉴定的靶基因。10 周龄时，雄性软骨特异性 -缺陷小鼠和对照小鼠接受半月板切除术（MNX）或假手术。MNX 后，在野生型小鼠中进行 SerpinA3N 或西维来司他（白细胞弹性蛋白酶（LE）的抑制剂，SerpinA3N 的底物）的关节内注射。术后 3-9 周通过组织学和微 CT 评估关节损伤。在暴露于巨噬细胞衍生的条件培养基的软骨外植体中评估西维来司他的作用。
RNA 测序显示 SerpinA3N 是软骨细胞中 IL-6 的主要靶基因。SerpinA3N 在 OA 软骨中的表达增加。软骨细胞中 SerpinA3N 的条件缺失加重了小鼠的 OA，而关节内注射 SerpinA3N 限制了关节损伤。软骨细胞不产生 SerpinA3N 靶向的丝氨酸蛋白酶。相比之下，巨噬细胞在受到 IL-6 刺激时产生 LE。西维来司他限制了由 IL-6 刺激的巨噬细胞衍生的条件培养基诱导的软骨分解代谢。此外，关节内注射西维来司他可防止 MNX 模型中的 OA。
SerpinA3N 可保护软骨免受包括 LE 在内的巨噬细胞产生的分解代谢因子的侵害。SerpinA3N 和 LE 代表了新的治疗靶点，可减轻 OA 中的软骨损伤。
