Targeted knockdown of PGAM5 in synovial macrophages efficiently alleviates osteoarthritis  

作　　者：Yuhang Liu Ruihan Hao Jia Lv Jie Yuan Xuelei Wang Churong Xu Ding Ma Zhouyi Duan Bingjun Zhang Liming Dai Yiyun Cheng Wei Lu Xiaoling Zhang 

机构地区：[1]Department of Orthopedic Surgery,Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine(SJTUSM),Shanghai 200092,China [2]National Facility for Translational Medicine,Shanghai 200240,China [3]Shanghai Frontiers Science Center of Genome Editing and Cell Therapy,Shanghai Key Laboratory of Regulatory Biology,School of Life Sciences,East China Normal University,Shanghai 200241,China [4]Department of Orthopaedic Surgery,The Second Hospital of Shanxi Medical University,Taiyuan 030001,China [5]CAS Key Laboratory of Tissue Microenvironment and Tumor,Shanghai Institute of Nutrition and Health,Chinese Academy of Sciences,Shanghai 200031,China [6]School of Medicine,Shanghai University,Shanghai 200444,China

出　　处：《Bone Research》2024年第1期215-226,共12页骨研究（英文版）

基　　金：This work was supported by grants from National Natural Science Foundation of China(81830078,82071868,32370892);Science and Technology Commission of Shanghai Municipality(23141901200);Health Commission of Shanghai Municipality(2022JC029);Biomaterials and Regenerative Medicine Institute Cooperative Research Project,Shanghai Jiaotong University School of Medicine(2022LHA11);Shanghai Key Laboratory of Orthopedic Implant(No.KFKT202206).

摘　　要：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-PPARγpathway in murine bone marrow-derived macrophages.Furthermore,we found that PGAM5 directly dephosphorylated Dishevelled Segment Polarity Protein 2(DVL2)which resulted in the inhibition ofβ-catenin and repolarization of M2 macrophages into M1 macrophages.Conditional knockout of both PGAM5 andβ-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.

关 键 词：OSTEOARTHRITIS METABOLISM inhibited 

分 类 号：R684.3[医药卫生—骨科学]