Objective

Osteoarthritis (OA), the leading cause of joint failure, is characterized by breakdown of articular cartilage and remodeling of subchondral bone in synovial joints. Despite the high prevalence and debilitating effects of OA, no disease-modifying drugs exist. Increasing evidence, including genetic variants of the interleukin 4 (IL-4) and IL-4 receptor genes, implicates a role for IL-4 in OA, however, the mechanism underlying IL-4 function in OA remains unknown. Here, we investigated the role of IL-4 in OA pathogenesis.

Methods

Il4-, myeloid-specific-Il4ra-, and Stat6-deficient and control mice were subjected to destabilization of the medial meniscus to induce OA. Macrophages, osteoclasts, and synovial explants were stimulated with IL-4 in vitro, and their function and expression profiles characterized.

Results

Mice lacking IL-4, IL-4Ra in myeloid cells, or STAT6 developed exacerbated cartilage damage and osteophyte formation relative to WT controls. In vitro analyses revealed that IL-4 downregulates osteoarthritis-associated genes, enhances macrophage phagocytosis of cartilage debris, and inhibits osteoclast differentiation and activation via the type I receptor.

Conclusion

Our findings demonstrate that IL-4 protects against osteoarthritis in a myeloid and STAT6-dependent manner. Further, IL-4 can promote an immunomodulatory microenvironment in which joint-resident macrophages polarize towards an M2 phenotype and efficiently clear pro-inflammatory debris, and osteoclasts maintain a homeostatic level of activity in subchondral bone. These findings support a role for IL-4 modulation of myeloid cell types in maintenance of joint health and identify a pathway that could provide therapeutic benefit for osteoarthritis.

中文翻译：

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白细胞介素 4 促进抗炎巨噬细胞清除软骨碎片并抑制破骨细胞发育以防止骨关节炎

客观的

骨关节炎 (OA) 是关节衰竭的主要原因，其特征在于关节软骨的破坏和滑膜关节中软骨下骨的重塑。尽管 OA 的患病率很高，而且会导致衰弱，但尚不存在改善疾病的药物。越来越多的证据，包括白介素 4 (IL-4) 和 IL-4 受体基因的遗传变异，暗示 IL-4 在 OA 中的作用，然而，IL-4 在 OA 中发挥作用的机制仍然未知。在这里，我们研究了 IL-4 在 OA 发病机制中的作用。

方法

Il4-、髓样特异性- Il4ra-和Stat6-缺陷小鼠和对照小鼠受到内侧半月板不稳定以诱导 OA。巨噬细胞、破骨细胞和滑膜外植体在体外用 IL-4 刺激，并表征了它们的功能和表达谱。

结果

与 WT 对照相比，缺乏 IL-4、IL-4Ra 或 STAT6 的小鼠出现了加剧的软骨损伤和骨赘形成。体外分析表明，IL-4 下调骨关节炎相关基因，增强巨噬细胞对软骨碎片的吞噬作用，并通过I 型受体抑制破骨细胞分化和活化。

结论

我们的研究结果表明，IL-4 以骨髓和 STAT6 依赖性方式预防骨关节炎。此外，IL-4 可以促进免疫调节微环境，其中关节驻留巨噬细胞向 M2 表型极化并有效清除促炎碎片，破骨细胞在软骨下骨中保持稳态活动水平。这些发现支持 IL-4 调节髓样细胞类型在维持关节健康中的作用，并确定了一种可为骨关节炎提供治疗益处的途径。