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

IF 20.3 1区 医学 Q1 RHEUMATOLOGY Annals of the Rheumatic Diseases Pub Date : 2024-11-14 DOI:10.1136/ard-2024-225645
Augustin Latourte, Sarah Jaulerry, Alice Combier, Chahrazad Cherifi, Yohan Jouan, Thierry Grange, Julien Daligault, Hang-Korng Ea, Martine Cohen-Solal, Eric Hay, Pascal Richette
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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.

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SerpinA3N 通过抑制巨噬细胞衍生的白细胞弹性蛋白酶来限制骨关节炎中软骨的破坏。
目的:众所周知,白细胞介素6(IL-6)等炎症介质可激活骨关节炎(OA)期间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 软骨损伤发展过程中的作用:在用IL-6处理的小鼠原代软骨细胞中进行了RNA测序,并在人类和小鼠OA软骨样本中确认了已确定的靶基因。雄性软骨特异性Serpina3n缺陷小鼠和对照小鼠在10周龄时接受了半月板切除术(MNX)或假手术。野生型小鼠在MNX后进行了SerpinA3N或西维司他(一种白细胞弹性蛋白酶(LE)抑制剂,SerpinA3N的底物)的关节内注射。术后 3-9 周通过组织学和显微 CT 评估关节损伤。在暴露于巨噬细胞条件培养基的软骨外植体中评估了西维司他的作用:结果: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。软骨细胞中条件性缺失 SerpinA3N 会加重小鼠的 OA,而关节内注射 SerpinA3N 则会限制关节损伤。软骨细胞不产生 SerpinA3N 靶向的丝氨酸蛋白酶。相反,巨噬细胞在IL-6刺激下产生LE。西维司他限制了IL-6刺激巨噬细胞产生的条件培养基诱导的软骨分解。此外,在MNX模型中,关节内注射西维司他可防止OA的发生:结论:SerpinA3N能保护软骨免受巨噬细胞(包括LE)产生的分解因子的影响。SerpinA3N和LE是抑制OA软骨损伤的新治疗靶点。
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来源期刊
Annals of the Rheumatic Diseases
Annals of the Rheumatic Diseases 医学-风湿病学
CiteScore
35.00
自引率
9.90%
发文量
3728
审稿时长
1.4 months
期刊介绍: Annals of the Rheumatic Diseases (ARD) is an international peer-reviewed journal covering all aspects of rheumatology, which includes the full spectrum of musculoskeletal conditions, arthritic disease, and connective tissue disorders. ARD publishes basic, clinical, and translational scientific research, including the most important recommendations for the management of various conditions.
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