Reprogramming of Mitochondrial Respiratory Chain Complex by Targeting SIRT3‐COX4I2 Axis Attenuates Osteoarthritis Progression

Liu, Yang; Hou, Mingzhuang; Xia, Xiaowei; Liu, Junlin; Xu, Yong; Shi, Qin; Zhang, Zhongmin; Wang, Liang; Shen, Yifan; Yang, Huilin; He, Fan; Zhang, Yijian

doi:10.1002/advs.202206144

Cited by 17 publications

(12 citation statements)

References 67 publications

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“…They also produce various cytokines, like arginase (Arg), IL-10, IL-1 receptor antagonist (IL-1ra), and the type II IL-1 decoy receptor. 14 , 30 , 31 Since investigations have shown that synovial macrophage polarization is closely associated with OA, 5 , 32 , 33 precise therapies for macrophage to decrease synovitis and attenuate OA progression need to be clearly proposed.…”

Section: Discussionmentioning

confidence: 99%

Targeted knockdown of PGAM5 in synovial macrophages efficiently alleviates osteoarthritis

Liu,

Hao,

et al. 2024

Bone Res

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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.

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Section: Discussionmentioning

confidence: 99%

Targeted knockdown of PGAM5 in synovial macrophages efficiently alleviates osteoarthritis

Liu,

Hao,

et al. 2024

Bone Res

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show abstract

“…They also produce various cytokines, like arginase (Arg), IL-10, IL-1 receptor antagonist (IL-1ra), and the type II IL-1 decoy receptor. [30][31][32] Since investigations have shown that synovial macrophage polarization is closely associated with OA, [33][34][35] precise therapies for macrophage to decrease synovitis and attenuate OA progression need to be clearly proposed.…”

Section: Discussionmentioning

confidence: 99%

Targeted knockdown of PGAM5 in synovial macrophages efficiently alleviates osteoarthritis

zhang,

Liu,

Hao

et al. 2023

Preprint

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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 in vivo and promoted anabolic metabolism of chondrocytes in vitro. 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.

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“…82 It was found that SIRT3 plays a role in maintaining mitochondrial homeostasis by deacetylating cytochrome c oxidase subunit 4 isoform 2 (COX4I2). 83 Additionally, SIRT6 was found to deacetylate STAT5, which inactivates IL-15/JAK3/STAT5. 84 These actions serve as negative regulators of the inflammatory response and RANKL-induced osteolysis.…”

Section: Molecular Modification Of Osteolysismentioning

confidence: 99%

Harnessing osteoimmunity to treat peri-implant inflammatory osteolysis

Chen,

Wang,

Yang

et al. 2024

Mater. Adv.

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Reprogramming of Mitochondrial Respiratory Chain Complex by Targeting SIRT3‐COX4I2 Axis Attenuates Osteoarthritis Progression

Cited by 17 publications

References 67 publications

Targeted knockdown of PGAM5 in synovial macrophages efficiently alleviates osteoarthritis

Targeted knockdown of PGAM5 in synovial macrophages efficiently alleviates osteoarthritis

Targeted knockdown of PGAM5 in synovial macrophages efficiently alleviates osteoarthritis

Harnessing osteoimmunity to treat peri-implant inflammatory osteolysis

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