Targeted knockdown of PGAM5 in synovial macrophages efficiently alleviates osteoarthritis
Abstract 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-...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2024-03-01
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| Series: | Bone Research |
| Online Access: | https://doi.org/10.1038/s41413-024-00318-8 |
| _version_ | 1827328240854761472 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Yuhang Liu |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-03-07T15:14:46Z |
| format | Article |
| id | doaj.art-2b5d58a879d34fe4b7a15657f5c46a70 |
| institution | Directory Open Access Journal |
| issn | 2095-6231 |
| language | English |
| last_indexed | 2024-03-07T15:14:46Z |
| publishDate | 2024-03-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Bone Research |
| spelling | doaj.art-2b5d58a879d34fe4b7a15657f5c46a702024-03-05T17:57:31ZengNature Publishing GroupBone Research2095-62312024-03-0112111210.1038/s41413-024-00318-8Targeted knockdown of PGAM5 in synovial macrophages efficiently alleviates osteoarthritisYuhang Liu0Ruihan Hao1Jia Lv2Jie Yuan3Xuelei Wang4Churong Xu5Ding Ma6Zhouyi Duan7Bingjun Zhang8Liming Dai9Yiyun Cheng10Wei Lu11Xiaoling Zhang12Department of Orthopedic Surgery, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (SJTUSM)Department of Orthopedic Surgery, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (SJTUSM)Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal UniversityDepartment of Orthopaedic Surgery, The Second Hospital of Shanxi Medical UniversityCAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of SciencesSchool of Medicine, Shanghai UniversityDepartment of Orthopedic Surgery, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (SJTUSM)Department of Orthopedic Surgery, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (SJTUSM)Department of Orthopedic Surgery, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (SJTUSM)Department of Orthopedic Surgery, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (SJTUSM)Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal UniversityCAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of SciencesDepartment of Orthopedic Surgery, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (SJTUSM)Abstract 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.https://doi.org/10.1038/s41413-024-00318-8 |
| spellingShingle | 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 Targeted knockdown of PGAM5 in synovial macrophages efficiently alleviates osteoarthritis Bone Research |
| title | Targeted knockdown of PGAM5 in synovial macrophages efficiently alleviates osteoarthritis |
| title_full | Targeted knockdown of PGAM5 in synovial macrophages efficiently alleviates osteoarthritis |
| title_fullStr | Targeted knockdown of PGAM5 in synovial macrophages efficiently alleviates osteoarthritis |
| title_full_unstemmed | Targeted knockdown of PGAM5 in synovial macrophages efficiently alleviates osteoarthritis |
| title_short | Targeted knockdown of PGAM5 in synovial macrophages efficiently alleviates osteoarthritis |
| title_sort | targeted knockdown of pgam5 in synovial macrophages efficiently alleviates osteoarthritis |
| url | https://doi.org/10.1038/s41413-024-00318-8 |
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