Breakthrough discovery: Targeting PGAM5 in macrophages could revolutionize osteoarthritis treatment

In a groundbreaking study, researchers have identified a significant increase in phosphoglycerate mutase 5 (PGAM5) in macrophages within osteoarthritic (OA) synovium compared to controls. This finding, based on histological analysis of human samples and single-cell RNA sequencing from mouse models, highlights a potential new therapeutic target for OA. The study published in Bone Research demonstrated that conditional knockout of PGAM5 in macrophages substantially alleviated OA symptoms and promoted the anabolic metabolism of chondrocytes both in vitro and in vivo 

Mechanistically, PGAM5 was found to enhance M1 macrophage polarization through the AKT-mTOR/p38/ERK pathways, while inhibiting M2 polarization via the STAT6-PPARγ pathway in murine bone marrow-derived macrophages. Further investigation revealed that PGAM5 directly dephosphorylates Dishevelled Segment Polarity Protein 2 (DVL2), inhibiting β-catenin and repolarizing M2 macrophages into M1 macrophages. Notably, conditional knockout of both PGAM5 and β-catenin in macrophages significantly exacerbate OA compared to PGAM5-deficient mice, underscoring the critical role of these pathways in disease progression. Building on these findings, the researchers developed mannose-modified fluoropolymers combined with siPGAM5, designed to specifically target synovial macrophages via intra-articular injection. This novel approach demonstrated precise targeting capabilities and significantly attenuated murine osteoarthritis. 

PGAM5 is a mitochondrial serine/threonine phosphatase integral to the mitochondrial membrane, playing a crucial role in regulating mitochondrial metabolism and dynamics, and overseeing various cellular functions. PGAM5 is essential in programmed cell necrosis, as it dephosphorylates Drp1, resulting in mitochondrial fragmentation. Additionally, PGAM5 governs mitophagy by either recruiting the E3 ubiquitin ligase PARKIN or dephosphorylating FUNDC1, thereby facilitating mitochondrial degradation. Beyond its role in mitochondrial regulation, PGAM5 influences cellular senescence and enhances inflammasome activation in macrophages, which is pivotal for the processing of pro-IL-1β in bone marrow-derived macrophages (BMDMs). 

The study findings establish PGAM5 as a pivotal factor in OA progression by modulating macrophage polarization, enhancing M1 macrophages via the AKT-mTOR/p38/ERK pathways and inhibiting M2 polarization through the STAT6-PPARγ pathway. The innovative use of mannose-modified fluoropolymers combined with siPGAM5 for targeted intra-articular delivery in murine models showed significant OA symptom relief, highlighting the therapeutic potential of PGAM5. 

Future research should focus on translating these findings to human clinical trials, optimizing delivery systems, and exploring combination therapies to enhance treatment efficacy. Comprehensive pathway analysis and developing biomarkers for early diagnosis and monitoring are also crucial. Additionally, investigating the role of PGAM5 in other joint diseases and conducting long-term safety studies will be essential for clinical adoption and improving patient outcomes in OA. 

 Reference 

Liu Y, Hao R, Lv J, Yuan J, Wang X, Xu C et al. Targeted knockdown of PGAM5 in synovial macrophages efficiently alleviates osteoarthritis. Bone Res. 2024 Mar 4;12(1):15.  

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