Pentraxin 3 regulated by miR-224-5p modulates macrophage reprogramming and exacerbates osteoarthritis associated synovitis by targeting CD32.
Pentraxin 3 regulated by miR-224-5p modulates macrophage reprogramming and exacerbates osteoarthritis associated synovitis by targeting CD32.
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miR-224-5p 调节的 Pentraxin 3 通过靶向 CD32 调节巨噬细胞重编程并加剧骨关节炎相关滑膜炎
DOI：
10.1038/s41419-022-04962-y
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发表时间：
2022-06-24
影响因子：
9
通讯作者：
Cai, Daozhang
中科院分区：
文献类型：
--
作者：
Yin, Jianbin;Zeng, Hua;Fan, Kai;Xie, Haoyu;Shao, Yan;Lu, Yuheng;Zhu, Jinjian;Yao, Zihao;Liu, Liangliang;Zhang, Hongbo;Luo, Bingsheng;Wang, Xinjie;Zeng, Chun;Bai, Xiaochun;Zhang, Haiyan;Cai, Daozhang
新出现的证据表明，M1/M2巨噬细胞极化的不平衡在骨关节炎（OA）进展中发挥重要作用。然而，这种极化的潜在机制基础是未知的。OA M1极化巨噬细胞的RNA测序发现高表达水平的正五聚蛋白3（PTX 3），表明PTX 3在OA发生和发展中的作用。在此，发现PTX 3在OA患者和OA小鼠的滑膜和关节软骨中增加。关节内注射PTX 3加重，而PTX 3中和逆转滑膜炎和软骨退变。当单独用PTX 3处理时，在软骨外植体中未观察到代谢紊乱或蛋白聚糖损失。然而，软骨外植体表现出OA表型时，用培养上清液的巨噬细胞刺激的PTX 3，这表明PTX 3对软骨细胞没有直接的影响。因此，PTX 3的OA抗软骨形成作用主要通过巨噬细胞介导。机制上，PTX 3通过miR-224- 5 p缺陷上调，其通过靶向CD 32激活p65/NF-κB通路以促进M1巨噬细胞极化。CD 32由巨噬细胞表达，当用PTX 3刺激时，巨噬细胞分泌大量的促炎细胞因子，诱导严重的关节软骨损伤。巨噬细胞和软骨细胞之间的旁分泌相互作用产生了一个反馈回路，增强了滑膜炎和软骨损伤。这项研究的结果确定了一个重要的OA发展的功能途径。阻断该通路和PTX 3可以预防和治疗OA。
Emerging evidence has shown an imbalance in M1/M2 macrophage polarization to play an essential role in osteoarthritis (OA) progression. However, the underlying mechanistic basis for this polarization is unknown. RNA sequencing of OA M1-polarized macrophages found highly expressed levels of pentraxin 3 (PTX3), suggesting a role for PTX3 in OA occurrence and development. Herein, PTX3 was found to be increased in the synovium and articular cartilage of OA patients and OA mice. Intra-articular injection of PTX3 aggravated, while PTX3 neutralization reversed synovitis and cartilage degeneration. No metabolic disorder or proteoglycan loss were observed in cartilage explants when treated with PTX3 alone. However, cartilage explants exhibited an OA phenotype when treated with culture supernatants of macrophages stimulated with PTX3, suggesting that PTX3 did not have a direct effect on chondrocytes. Therefore, the OA anti-chondrogenic effects of PTX3 are primarily mediated through macrophages. Mechanistically, PTX3 was upregulated by miR-224-5p deficiency, which activated the p65/NF-κB pathway to promote M1 macrophage polarization by targeting CD32. CD32 was expressed by macrophages, that when stimulated with PTX3, secreted abundant pro-inflammation cytokines that induced severe articular cartilage damage. The paracrine interaction between macrophages and chondrocytes produced a feedback loop that enhanced synovitis and cartilage damage. The findings of this study identified a functional pathway important to OA development. Blockade of this pathway and PTX3 may prevent and treat OA.
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影响因子：
27.4
作者：
Atukorala I;Kwoh CK;Guermazi A;Roemer FW;Boudreau RM;Hannon MJ;Hunter DJ
通讯作者：
Hunter DJ
影响因子：
--
作者：
Ekenstedt, Kari J.;Sonntag, William E.;Carlson, Cathy S.
通讯作者：
Carlson, Cathy S.
影响因子：
7
作者：
Ali, S. A.;Gandhi, R.;Kapoor, M.
通讯作者：
Kapoor, M.
影响因子：
3.1
作者：
Kato, Shingo;Ochiai, Mitsuko;Yakabi, Koji
通讯作者：
Yakabi, Koji
影响因子：
7.9
作者：
Carrizzo, Albino;Procaccini, Claudio;Vecchione, Carmine
通讯作者：
Vecchione, Carmine