Introduction
Knee osteoarthritis (KOA) has traditionally been considered a degenerative joint disease primarily driven by mechanical wear. However, growing evidence supports the concept that low-grade chronic inflammation within the synovium significantly contributes to disease progression [1, 2]. Among the cellular components of the synovial membrane, macrophages represent a dominant immune population that plays a critical role in maintaining joint homeostasis as well as mediating pathological inflammation. Recent advances in basic science have emphasized that not only the presence of macrophages but also their functional phenotype is crucial in determining disease outcomes.
Macrophages exhibit remarkable plasticity and can polarize into distinct functional phenotypes in response to environmental cues. Classically activated macrophages (M1) are induced by stimuli such as interferon-γ and lipopolysaccharide and are characterized by the production of pro-inflammatory cytokines, including interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) [3]. In contrast, alternatively activated macrophages (M2) are associated with anti-inflammatory functions, tissue repair, and the secretion of cytokines such as IL-10 and transforming growth factor-β (TGF-β) [4, 5]. In healthy joints, a balance between these phenotypes contributes to immune regulation and tissue maintenance.
In the osteoarthritic knee, this balance is disrupted, leading to a predominance of the M1 phenotype within the synovium [6, 7]. This shift promotes a pro-inflammatory microenvironment that enhances cartilage degradation by upregulating matrix metalloproteinases (MMPs) and aggrecanases. Moreover, M1 macrophages amplify inflammatory signaling pathways, such as nuclear factor kappa B (NF-κB), further exacerbating tissue damage [8]. Synovial inflammation mediated by M1 macrophages has also been associated with pain severity in KOA, suggesting a direct link between immune dysregulation and clinical symptoms [9-11].
Conversely, M2 macrophages play a protective role by promoting resolution of inflammation and supporting tissue repair. However, in KOA, the number and activity of M2 macrophages are often insufficient to counterbalance the pro-inflammatory effects of M1 cells [12, 13]. This imbalance not only sustains chronic inflammation but also impairs regenerative processes within the joint. Emerging evidence suggests that modulating macrophage polarization toward the M2 phenotype may represent a promising therapeutic strategy for osteoarthritis.
At the molecular level, several signaling pathways regulate macrophage polarization in the synovial environment. Key regulators include the NF-κB pathway, signal transducer and activator of transcription signaling, and hypoxia-inducible factors (HIFs), which respond to the hypoxic conditions in osteoarthritic joints [14-17]. In addition, metabolic reprogramming has been shown to influence macrophage phenotype, with M1 macrophages relying on glycolysis and M2 macrophages favoring oxidative phosphorylation [18-20]. These findings highlight the complex interplay between metabolic and inflammatory pathways in shaping macrophage function.
Recent studies have also identified the role of extracellular vesicles, particularly exosomes, in modulating macrophage polarization. Exosomes derived from mesenchymal stem cells have been shown to promote M2 polarization and reduce inflammation in experimental models of osteoarthritis [21, 22]. Furthermore, non-coding RNAs, including microRNAs, are increasingly recognized as key regulators of macrophage phenotype by targeting genes involved in inflammatory signaling [23, 24]. These advances open new avenues for targeted therapies to restore immune balance in osteoarthritic joints.
Overall, synovial macrophage polarization represents a critical but relatively underexplored aspect of the pathophysiology of KOA. The dynamic balance between M1 and M2 phenotypes not only influences inflammation and cartilage degradation but also determines the potential for tissue repair. Understanding the mechanisms that regulate this balance may lead to the development of novel disease-modifying therapies.

Conclusion
Synovial macrophage polarization plays a pivotal role in the pathogenesis of KOA by regulating the balance between pro-inflammatory and anti-inflammatory processes. The predominance of M1 macrophages contributes to chronic inflammation and cartilage degradation, while insufficient M2 activity limits tissue repair. Targeting macrophage polarization represents a promising and relatively underexplored therapeutic strategy that bridges basic immunology and clinical management of KOA.

Ethical Considerations
Compliance with ethical guidelines
There were no ethical considerations to be considered in this research.

Funding
This research did not receive any grant from funding agencies in the public, commercial, or non-profit sectors. 

Authors' contributions
All authors contributed equally to the conception and design of the study, data collection and analysis, interception of the results and drafting of the manuscript. Each author approved the final version of the manuscript  for submission.

Conflict of interest
The authors declared no conflict of interest.


References

1. Robinson WH, Lepus CM, Wang Q, Raghu H, Mao R, Lindstrom TM, et al. Low-grade inflammation as a key mediator of the pathogenesis of osteoarthritis. Nat Rev Rheumatol. 2016; 12(10):580-92. [DOI:10.1038/nrrheum.2016.136] [PMID]
2. Scanzello CR, Goldring SR. The role of synovitis in osteoarthritis pathogenesis. Bone. 2012; 51(2):249-257. [DOI:10.1016/j.bone.2012.02.012] [PMID]
3. Murray PJ. Macrophage polarization. Annu Rev Physiol. 2017; 79:541-66. [DOI:10.1146/annurev-physiol-022516-034339] [PMID]
4. Mantovani A, Sica A, Locati M. Macrophage polarization comes of age. Immunity. 2005; 23(4):344-6. [DOI:10.1016/j.immuni.2005.10.001] [PMID]
5. Mantovani A, Locati M. Tumor-associated macrophages as a paradigm of macrophage plasticity, diversity, and polarization: lessons and open questions. Arterioscler Thromb Vasc Biol. 2013; 33(7):1478-83. [DOI:10.1161/ATVBAHA.113.300168] [PMID]
6. Zhang H, Cai D, Bai X. Macrophages regulate the progression of osteoarthritis. Osteoarthritis Cartilage. 2020; 28(5):555-61. [DOI:10.1016/j.joca.2020.01.007] [PMID]
7. Zhang H, Lin C, Zeng C, Wang Z, Wang H, Lu J, et al. Synovial macrophage M1 polarisation exacerbates experimental osteoarthritis partially through R-spondin-2. Ann Rheum Dis. 2018; 77(10):1524-34. [DOI:10.1136/annrheumdis-2018-213450] [PMID]
8. Liu-Bryan R, Terkeltaub R. Emerging regulators of the inflammatory process in osteoarthritis. Nat Rev Rheumatol. 2015; 11(1):35-44.  [DOI:10.1038/nrrheum.2014.162] [PMID]
9. Bondeson J, Blom AB, Wainwright S, Hughes C, Caterson B, van den Berg WB. The role of synovial macrophages and macrophage-produced mediators in driving inflammatory and destructive responses in osteoarthritis. Arthritis Rheum. 2010; 62(3):647-5. [DOI:10.1002/art.27290] [PMID]
10. Bondeson J. Activated synovial macrophages as targets for osteoarthritis drug therapy.  Curr Drug Targets. 2010; 11(5):576-85. [DOI:10.2174/138945010791011965] [PMID]
11. Bondeson J. The role of synovial macrophages in rheumatoid arthritis and osteoarthritis: Its implications for radiosynovectomy. In: Kampen W, Fischer M, editor. Local Treatment of Inflammatory Joint Diseases: Benefits and Risks. Cham: Springer; 2015. [DOI:10.1007/978-3-319-16949-1_2]
12. Haraden CA, Huebner JL, Hsueh MF, Li YJ, Kraus VB. Synovial fluid biomarkers associated with osteoarthritis severity reflect macrophage and neutrophil related inflammation. Arthritis Res Ther. 2019; 21(1):146. [DOI:10.1186/s13075-019-1923-x] [PMID]
13. Kraus VB, Karsdal MA. Osteoarthritis: Current molecular biomarkers and the way forward. Calcif Tissue Int. 2021; 109(3):329-38. [DOI:10.1007/s00223-020-00701-7] [PMID]
14. Palazon A, Goldrath AW, Nizet V, Johnson RS.  HIF transcription factors, inflammation, and immunity. Immunity. 2014; 41(4):518-28. [DOI:10.1016/j.immuni.2014.09.008] [PMID]
15. Almanzar G, Alarcon JC, Garzon R, Navarro AM, Ondo-Méndez A, Prelog M. Hypoxia and activation of hypoxia inducible factor alpha as influencers of inflammatory helper T cells in autoimmune disease - a link between cancer and autoimmunity. Front Immunol. 2025; 16:1633845.[DOI:10.3389/fimmu.2025.1633845] [PMID]
16. Wu D, Xu J, Jiao W, Liu L, Yu J, Zhang M, et al. Suppression of macrophage activation by sodium danshensu via HIF-1α/STAT3/NLRP3 pathway ameliorated collagen-induced arthritis in mice. Molecules. 2023; 28(4):1551. [DOI:10.3390/molecules28041551] [PMID]
17. Zhang XA, Kong H. Mechanism of HIFs in osteoarthritis. Front Immunol. 2023; 14:1168799. [DOI:10.3389/fimmu.2023.1168799] [PMID]
18. Shapiro H, Lutaty A, Ariel A. Macrophages, meta-inflammation, and immuno-metabolism. ScientificWorldJournal. 2011; 11:2509-29. [DOI:10.1100/2011/397971] [PMID]
19. Wang L, Wang D, Zhang T, Ma Y, Tong X, Fan H. The role of immunometabolism in macrophage polarization and its impact on acute lung injury/acute respiratory distress syndrome. Front Immunol. 2023; 14:1117548. [DOI:10.3389/fimmu.2023.1117548] [PMID]
20. Li J, Zhang L, Peng J, Zhao C, Li W, Yu Y, et al. Mitochondrial metabolic regulation of macrophage polarization in osteomyelitis and other orthopedic disorders: Mechanisms and therapeutic opportunities. Front Cell Dev Biol. 2025; 13:1604320.  [DOI:10.3389/fcell.2025.1604320] [PMID]
21. Cosenza S, Ruiz M, Toupet K, Jorgensen C, Noël D. Mesenchymal stem cells derived exosomes and microparticles protect cartilage and bone from degradation in osteoarthritis. Sci Rep. 2017; 7(1):16214.  [DOI:10.1038/s41598-017-15376-8] [PMID]
22. Cosenza S, Toupet K, Maumus M, Luz-Crawford P, Blanc-Brude O, Jorgensen C, et al. Mesenchymal stem cells-derived exosomes are more immunosuppressive than microparticles in inflammatory arthritis. Theranostics. 2018; 8(5):1399-410.[DOI:10.7150/thno.21072] [PMID]
23. Chen B, Hong H, Sun Y, Chen C, Wu C, Xu G, et al., Role of macrophage polarization in osteoarthritis. Exp Ther Med. 2022; 24(6):757.  [DOI:10.3892/etm.2022.11693] [PMID]
24. Chen P, Ruan A, Zhou J, Zeng L, Liu J, Wang Q. Identification and analysis of key microRNAs derived from osteoarthritis synovial fluid exosomes. Chin Med J (Engl). 2023; 136(2):245-7. [DOI:10.1097/CM9.0000000000002101] [PMID]