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Targeted knockdown of PGAM5 in synovial macrophages efficiently alleviates osteoarthritis
Bone Research ( IF 14.3 ) Pub Date : 2024-03-04 , DOI: 10.1038/s41413-024-00318-8
Yuhang Liu 1, 2 , Ruihan Hao 1, 2 , Jia Lv 3 , Jie Yuan 4 , Xuelei Wang 5 , Churong Xu 6 , Ding Ma 1, 2 , Zhouyi Duan 1, 2 , Bingjun Zhang 1, 2 , Liming Dai 1, 2 , Yiyun Cheng 3 , Wei Lu 5 , Xiaoling Zhang 1, 2
Affiliation  

Osteoarthritis (OA) is a common degenerative disease worldwide and new therapeutics that target inflammation and the crosstalk between immunocytes and chondrocytes are being developed to prevent and treat OA. These attempts involve repolarizing pro-inflammatory M1 macrophages into the anti-inflammatory M2 phenotype in synovium. In this study, we found that phosphoglycerate mutase 5 (PGAM5) significantly increased in macrophages in OA synovium compared to controls based on histology of human samples and single-cell RNA sequencing results of mice models. To address the role of PGAM5 in macrophages in OA, we found conditional knockout of PGAM5 in macrophages greatly alleviated OA symptoms and promoted anabolic metabolism of chondrocytes in vitro and in vivo. Mechanistically, we found that PGAM5 enhanced M1 polarization via AKT-mTOR/p38/ERK pathways, whereas inhibited M2 polarization via STAT6-PPARγ pathway in murine bone marrow-derived macrophages. Furthermore, we found that PGAM5 directly dephosphorylated Dishevelled Segment Polarity Protein 2 (DVL2) which resulted in the inhibition of β-catenin and repolarization of M2 macrophages into M1 macrophages. Conditional knockout of both PGAM5 and β-catenin in macrophages significantly exacerbated osteoarthritis compared to PGAM5-deficient mice. Motivated by these findings, we successfully designed mannose modified fluoropolymers combined with siPGAM5 to inhibit PGAM5 specifically in synovial macrophages via intra-articular injection, which possessed desired targeting abilities of synovial macrophages and greatly attenuated murine osteoarthritis. Collectively, these findings defined a key role for PGAM5 in orchestrating macrophage polarization and provides insights into novel macrophage-targeted strategy for treating OA.



中文翻译:


滑膜巨噬细胞中 PGAM5 的靶向敲低可有效缓解骨关节炎



骨关节炎 (OA) 是一种世界范围内常见的退行性疾病,针对炎症以及免疫细胞和软骨细胞之间的串扰的新疗法正在开发中,以预防和治疗 OA。这些尝试涉及将滑膜中的促炎性 M1 巨噬细胞重新极化为抗炎性 M2 表型。在这项研究中,我们根据人类样本的组织学和小鼠模型的单细胞 RNA 测序结果发现,与对照相比,OA 滑膜中的巨噬细胞中磷酸甘油酸变位酶 5 (PGAM5) 显着增加。为了解决巨噬细胞中 PGAM5 在 OA 中的作用,我们发现巨噬细胞中 PGAM5 的条件性敲除可以极大地缓解 OA 症状,并促进体外和体内软骨细胞的合成代谢。从机制上讲,我们发现在小鼠骨髓源性巨噬细胞中,PGAM5 通过 AKT-mTOR/p38/ERK 通路增强 M1 极化,而通过 STAT6-PPARγ 通路抑制 M2 极化。此外,我们发现 PGAM5 直接使散乱片段极性蛋白 2 (DVL2) 去磷酸化,从而抑制 β-连环蛋白并使 M2 巨噬细胞复极化为 M1 巨噬细胞。与PGAM5缺陷小鼠相比,巨噬细胞中PGAM5和β-连环蛋白的条件性敲除显着加剧了骨关节炎。受这些发现的启发,我们成功设计了甘露糖修饰的含氟聚合物与siPGAM5结合,通过关节内注射特异性抑制滑膜巨噬细胞中的PGAM5,具有所需的滑膜巨噬细胞靶向能力,并大大减轻了小鼠骨关节炎。总的来说,这些发现明确了 PGAM5 在协调巨噬细胞极化中的关键作用,并为治疗 OA 的新型巨噬细胞靶向策略提供了见解。

更新日期:2024-03-04
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