Macrophage Polarization in the Osteoarthritis Pathogenesis and Treatment

Abstract

Osteoarthritis (OA) is a prevalent degenerative disorder that severely impacts quality of life due to pain and disability. Although the pathophysiology of OA remains incompletely understood, recent research highlights the role of synovial inflammation in OA onset and progression, driven primarily by inflammatory infiltrates, especially macrophages, in the synovium. These macrophages respond to the local microenvironment, polarizing into either pro-inflammatory (M1) or anti-inflammatory (M2) subtypes. This review focuses on the role of macrophage polarization in OA pathogenesis and treatment, emphasizing how M1/M2 polarization is influenced by pathways such as STAT, NF-κB, caspase, and MAPK. These pathways induce low-grade inflammation within OA-affected joints, altering chondrocyte metabolism, inhibiting cartilage repair, and impairing mesenchymal stem cell chondrogenesis, thereby contributing to OA progression. Additionally, this review discusses potential therapies targeting macrophage polarization, encompassing compounds, proteins, cells, and microRNAs, to offer insights into novel treatment strategies for OA.

Keywords

macrophages / osteoarthritis / pathogenesis / polarization / progression / treatment

References

[1] G. Musumeci, F. C. Aiello, M. A. Szychlinska, M. Di Rosa, P. Castrogiovanni, and A. Mobasheri, “Osteoarthritis in the XXIst Century: Risk Factors and Behaviours That Influence Disease Onset and Progression,” International Journal of Molecular Sciences 16, no. 3 (2015): 6093–6112.

[2] S. Glyn-Jones, A. J. Palmer, R. Agricola, et al., “Osteoarthritis,” Lancet 386, no. 9991 (2015): 376–387.

[3] C. Ke, H. Li, D. Yang, et al., “Melatonin Attenuates the Progression of Osteoarthritis in Rats by Inhibiting Inflammation and Related Oxidative Stress on the Surface of Knee Cartilage,” Orthopaedic Surgery 14, no. 9 (2022): 2230–2237.

[4] M. H. Li, R. Xiao, J. B. Li, and Q. Zhu, “Regenerative Approaches for Cartilage Repair in the Treatment of Osteoarthritis,” Osteoarthritis and Cartilage 25, no. 10 (2017): 1577–1587.

[5] GBD 2021 Osteoarthritis Collaborators, “Global, Regional, and National Burden of Osteoarthritis, 1990–2020 and Projections to 2050: A Systematic Analysis for the Global Burden of Disease Study 2021,” Lancet Rheumatology 5, no. 9 (2023): e508–e522.

[6] A. Ghouri and P. G. Conaghan, “Prospects for Therapies in Osteoarthritis,” Calcified Tissue International 109, no. 3 (2021): 339–350.

[7] G. D. Deyle, C. S. Allen, S. C. Allison, et al., “Physical Therapy Versus Glucocorticoid Injection for Osteoarthritis of the Knee,” New England Journal of Medicine 382, no. 15 (2020): 1420–1429.

[8] A. Nowaczyk, D. Szwedowski, I. Dallo, and J. Nowaczyk, “Overview of First-Line and Second-Line Pharmacotherapies for Osteoarthritis With Special Focus on Intra-Articular Treatment,” International Journal of Molecular Sciences 23, no. 3 (2022): 1566.

[9] H. Peng, A. Ou, X. Huang, et al., “Osteotomy Around the Knee: The Surgical Treatment of Osteoarthritis,” Orthopaedic Surgery 13, no. 5 (2021): 1465–1473.

[10] Z. Cai, Y. Cui, J. Wang, et al., “A Narrative Review of the Progress in the Treatment of Knee Osteoarthritis,” Annals of Translational Medicine 10, no. 6 (2022): 373.

[11] M. H. M Yunus, A. Nordin, and H. Kamal, “Pathophysiological Perspective of Osteoarthritis,” Medicina (Kaunas, Lithuania) 56, no. 11 (2020): 614.

[12] W. Xiang, Q. Zheng, A. Liu, et al., “Recent Therapeutic Strategies for Excessive Chondrocyte Death in Osteoarthritis: A Review,” Orthopaedic Surgery 15, no. 6 (2023): 1437–1453.

[13] P. Hoff, F. Buttgereit, G. R. Burmester, et al., “Osteoarthritis Synovial Fluid Activates Pro-Inflammatory Cytokines in Primary Human Chondrocytes,” International Orthopaedics 37, no. 1 (2013): 145–151.

[14] W. H. Robinson, C. M. Lepus, Q. Wang, et al., “Low-Grade Inflammation as a Key Mediator of the Pathogenesis of Osteoarthritis,” Nature Reviews Rheumatology 12, no. 10 (2016): 580–592.

[15] C. Zeng, Y. S. Li, and G. H. Lei, “Synovitis in Knee Osteoarthritis: A Precursor or a Concomitant Feature?,” Annals of the Rheumatic Diseases 74, no. 10 (2015): e58.

[16] I. Atukorala, C. K. Kwoh, A. Guermazi, et al., “Synovitis in Knee Osteoarthritis: A Precursor of Disease?,” Annals of the Rheumatic Diseases 75, no. 2 (2016): 390–395.

[17] L. C. Davies, S. J. Jenkins, J. E. Allen, and P. R. Taylor, “Tissue-Resident Macrophages,” Nature Immunology 14, no. 10 (2013): 986–995.

[18] C. L. Wu, N. S. Harasymowicz, M. A. Klimak, K. H. Collins, and F. Guilak, “The Role of Macrophages in Osteoarthritis and Cartilage Repair,” Osteoarthritis and Cartilage 28, no. 5 (2020): 544–554.

[19] H. Zhang, D. Cai, and X. Bai, “Macrophages Regulate the Progression of Osteoarthritis,” Osteoarthritis and Cartilage 28, no. 5 (2020): 555–561.

[20] L. Utomo, Y. M Bastiaansen-Jenniskens, J. A. N. Verhaar, and G. J. V. M. van Osch, “Cartilage Inflammation and Degeneration Are Enhanced by Pro-Inflammatory (M1) Macrophages In Vitro, but Not Inhibited Directly by Anti-Inflammatory (M2) Macrophages,” Osteoarthritis and Cartilage 24, no. 12 (2016): 2162–2170.

[21] H. W. Lee, H. J. Choi, S. J. Ha, K. T. Lee, and Y. G. Kwon, “Recruitment of Monocytes/Macrophages in Different Tumor Microenvironments,” Biochimica et Biophysica Acta 1835, no. 2 (2013): 170–179.

[22] S. Zhang, S. J. Chuah, R. C. Lai, J. H. P. Hui, S. K. Lim, and W. S. Toh, “MSC Exosomes Mediate Cartilage Repair by Enhancing Proliferation, Attenuating Apoptosis and Modulating Immune Reactivity,” Biomaterials 156 (2018): 16–27.

[23] K. O’ Brien and P. Tailor, “Enumeration and Localization of Mesenchymal Progenitor Cells and Macrophages in Synovium From Normal Individuals and Patients With Pre-Osteoarthritis or Clinically Diagnosed Osteoarthritis,” International Journal of Molecular Sciences 18, no. 4 (2017): 15.

[24] V. B. Kraus, G. McDaniel, J. L. Huebner, et al., “Direct In Vivo Evidence of Activated Macrophages in Human Osteoarthritis,” Osteoarthritis and Cartilage 24, no. 9 (2016): 1613–1621.

[25] C. Manferdini and F. Paolella, “From Osteoarthritic Synovium to Synovialderived Cells Characterization: Synovial Macrophages Are Key Effector Cells,” Arthritis Research & Therapy 18 (2016): 83.

[26] C. S. B. Viegas and R. M. Costa, “Gla-Rich Protein Function as an Anti-Inflammatory Agent in Monocytes/Macrophages: Implications for Calcification-Related Chronic Inflammatory Diseases,” PLoS One 12, no. 5 (2017): e0177829.

[27] I. A. Udalova, A. Mantovani, and M. Feldmann, “Macrophage Heterogeneity in the Context of Rheumatoid Arthritis,” Nature Reviews Rheumatology 12, no. 8 (2016): 472–485.

[28] T. M. Griffin and C. R. Scanzello, “Innate Inflammation and Synovial Macrophages in Osteoarthritis Pathophysiology,” Clinical and Experimental Rheumatology 37 Suppl 120, no. 5 (2019): 57–63.

[29] J. P. Edwards, X. Zhang, K. A. Frauwirth, and D. M. Mosser, “Biochemical and Functional Characterization of Three Activated Macrophage Populations,” Journal of Leukocyte Biology 80, no. 6 (2006): 1298–1307.

[30] B. Liu, M. Zhang, J. Zhao, M. Zheng, and H. Yang, “Imbalance of M1/M2 Macrophages Is Linked to Severity Level of Knee Osteoarthritis,” Experimental and Therapeutic Medicine 16, no. 6 (2018): 5009–5014.

[31] T. Rőszer, “Understanding the Mysterious M2 Macrophage Through Activation Markers and Effector Mechanisms,” Mediators of Inflammation 2015 (2015): 816460.

[32] M. Benoit, B. Desnues, and J. L. Mege, “Macrophage Polarization in Bacterial Infections,” Journal of Immunology 181, no. 6 (2008): 3733–3739.

[33] S. Gordon and P. R. Taylor, “Monocyte and Macrophage Heterogeneity,” Nature Reviews. Immunology 5, no. 12 (2005): 953–964.

[34] A. Mantovani, S. K. Biswas, M. R. Galdiero, A. Sica, and M. Locati, “Macrophage Plasticity and Polarization in Tissue Repair and Remodelling,” Journal of Pathology 229, no. 2 (2013): 176–185.

[35] K. Voss, H. S. Hong, J. E. Bader, A. Sugiura, C. A. Lyssiotis, and J. C. Rathmell, “A Guide to Interrogating Immunometabolism,” Nature Reviews. Immunology 21, no. 10 (2021): 637–652.

[36] B. Liu, Y. Xian, X. Chen, et al., “Inflammatory Fibroblast-Like Synoviocyte-Derived Exosomes Aggravate Osteoarthritis via Enhancing Macrophage Glycolysis,” Advanced Science 11, no. 14 (2024): e2307338.

[37] Y. Liu, R. Xu, H. Gu, et al., “Metabolic Reprogramming in Macrophage Responses,” Biomarker Research 9, no. 1 (2021): 1.

[38] D. G. Russell, L. Huang, and B. C. VanderVen, “Immunometabolism at the Interface Between Macrophages and Pathogens,” Nature Reviews. Immunology 19, no. 5 (2019): 291–304.

[39] O. R. Mahon, D. J. Kelly, G. M. McCarthy, and A. Dunne, “Osteoarthritis-Associated Basic Calcium Phosphate Crystals Alter Immune Cell Metabolism and Promote M1 Macrophage Polarization,” Osteoarthritis and Cartilage 28, no. 5 (2020): 603–612.

[40] P. Chandrasekaran, S. Izadjoo, J. Stimely, et al., “Regulatory Macrophages Inhibit Alternative Macrophage Activation and Attenuate Pathology Associated With Fibrosis,” Journal of Immunology 203, no. 8 (2019): 2130–2140.

[41] C. J. Ferrante and S. J. Leibovich, “Regulation of Macrophage Polarization and Wound Healing,” Advances in Wound Care 1, no. 1 (2012): 10–16.

[42] H. Zhang, C. Lin, C. Zeng, et al., “Synovial Macrophage M1 Polarisation Exacerbates Experimental Osteoarthritis Partially Through R-Spondin-2,” Annals of the Rheumatic Diseases 77, no. 10 (2018): 1524–1534.

[43] M. Locati, G. Curtale, and A. Mantovani, “Diversity, Mechanisms, and Significance of Macrophage Plasticity,” Annual Review of Pathology 24, no. 15 (2020): 123–147.

[44] R. Liu-Bryan and R. Terkeltaub, “Emerging Regulators of the Inflammatory Process in Osteoarthritis,” Nature Reviews Rheumatology 11, no. 1 (2015): 35–44.

[45] E. Barboza, J. Hudson, W. P. Chang, et al., “Profibrotic Infrapatellar Fat Pad Remodeling Without M1 Macrophage Polarization Precedes Knee Osteoarthritis in Mice With Diet-Inducedobesity,” Arthritis & Rhematology 69, no. 6 (2017): 1221–1232.

[46] C. Wu, Y. Zhao, X. Xiao, et al., “Graft-Infiltrating Macrophages Adopt an M2 Phenotype and Are Inhibited by Purinergic Receptor P2X7 Antagonist in Chronic Rejection,” American Journal of Transplantation 16, no. 9 (2016): 2563–2573.

[47] M. J. Benito, D. J. Veale, O. FitzGerald, W. van den Berg, and B. Bresnihan, “Synovial Tissue Inflammation in Early and Late Osteoarthritis,” Annals of the Rheumatic Diseases 64, no. 9 (2005): 1263–1267.

[48] N. Topoluk, K. Steckbeck, S. Siatkowski, B. Burnikel, J. Tokish, and J. Mercuri, “Amniotic Mesenchymal Stem Cells Mitigate Osteoarthritis Progression in a Synovial Macrophage-Mediated In Vitro Explant Coculture Model,” Journal of Tissue Engineering and Regenerative Medicine 12, no. 4 (2018): 1097–1110.

[49] S. Samavedi, P. Diaz-Rodriguez, J. D Erndt-Marino, and M. S. Hahn, “Three Dimensional Chondrocyte Macrophage Coculture System to Probe Inflammation in Experimental Osteoarthritis,” Tissue Engineering. Part A 23, no. 3–4 (2017): 101–114.

[50] M. Dai, B. Sui, Y. Xue, et al., “Cartilage Repair in Degenerative Osteoarthritis Mediated by Squid Type II Collagen via Immunomodulating Activation of M2 Macrophages, Inhibiting Apoptosis and Hypertrophy of Chondrocytes,” Biomaterials 180 (2018): 91–103.

[51] A. R. Sun, S. K. Panchal, T. Friis, et al., “Obesity-Associated Metabolic Syndrome Spontaneously Induces Infiltration of Proinflammatory Macrophage in Synovium and Promotes Osteoarthritis,” PLoS One 12, no. 8 (2017): e0183693.

[52] N. Sambamurthy, C. Zhou, V. Nguyen, et al., “Deficiency of the Pattern-Recognition Receptor CD14 Protects Against Joint Pathology and Functional Decline in a Murine Model of Osteoarthritis,” PLoS One 13, no. 11 (2018): e0206217.

[53] N. Fahy, M. L. de Vries-van Melle, J. Lehmann, et al., “Human Osteoarthritic Synovium Impacts Chondrogenic Differentiation of Mesenchymal Stem Cells via a Macrophage Polarisation State,” Osteoarthritis and Cartilage 22, no. 8 (2014): 1167–1175.

[54] C. De Bari, F. Dell’Accio, P. Tylzanowski, and F. P. Luyten, “Multipotent Mesenchymal Stem Cells From Adult Human Synovial Membrane,” Arthritis and Rheumatism 44, no. 8 (2001): 1928–1942.

[55] I. Malyshev and Y. Malyshev, “Current Concept and Update of the Macrophage Plasticity Concept: Intracellular Mechanisms of Reprogramming and M3 Macrophage “Switch” Phenotype,” BioMed Research International 2015 (2015): 341308.

[56] P. J. Murray, E. Allen, S. K. Biswas, et al., “Macrophage Activation and Polarization: Nomenclature and Experimental Guidelines,” Immunity 41, no. 1 (2014): 14–20.

[57] M. J. Wood, A. Leckenby, G. Reynolds, et al., “Macrophage Proliferation Distinguishes 2 Subgroups of Knee Osteoarthritis Patients,” JCI Insight 4, no. 2 (2019): e125325.

[58] R. Han, M. Hu, Q. Zhong, et al., “Perfluorooctane Sulphonate Induces Oxidative Hepatic Damage via Mitochondriadependent and NF-κB/TNF-α-Mediated Pathway,” Chemosphere 191 (2018): 1056–1064.

[59] J. Wu, Y. M. Zhao, and Z. K. Deng, “Tangeretin Ameliorates Renal Failure via Regulating Oxidative Stress, NF-κB–TNF-α/iNOS Signalling and Improves Memory and Cognitive Deficits in 5/6 Nephrectomized Rats,” Inflammopharmacology 26, no. 1 (2018): 119–132.

[60] T. Gaojian, Q. Dingfei, L. Linwei, et al., “Parthenolide Promotes the Repair of Spinal Cord Injury by Modulating M1/M2 Polarization via the NF-κB and STAT1/3 Signaling Pathway,” Cell Death Discovery 6, no. 1 (2020): 97.

[61] M. Li, X. Sun, J. Zhao, et al., “CCL5 Deficiency Promotes Liver Repair by Improving Inflammation Resolution and Liver Regeneration Through M2 Macrophage Polarization,” Cellular & Molecular Immunology 17, no. 7 (2020): 753–764.

[62] F. Zhou, J. Mei, X. Han, et al., “Kinsenoside Attenuates Osteoarthritis by Repolarizing Macrophages Through Inactivating NF-κB/MAPK Signaling and Protecting Chondrocytes,” Acta Pharmaceutica Sinica B 9, no. 5 (2019): 973–985.

[63] J. Lu, H. Zhang, J. Pan, et al., “Fargesin Ameliorates Osteoarthritis via Macrophage Reprogramming by Downregulating MAPK and NF-κB Pathways,” Arthritis Research & Therapy 23, no. 1 (2021): 142.

[64] J. Lu, H. Guan, D. Wu, et al., “Pseudolaric Acid B Ameliorates Synovial Inflammation and Vessel Formation by Stabilizing PPARγ to Inhibit NF-κB Signalling Pathway,” Journal of Cellular and Molecular Medicine 25, no. 14 (2021): 6664–6678.

[65] A. Uchiyama, S. I. Motegi, A. Sekiguchi, et al., “Mesenchymal Stem Cells-Derived MFG-E8 Accelerates Diabetic Cutaneous Wound Healing,” Journal of Dermatological Science 86 (2017): 187–197.

[66] Y. Lu, L. Liu, J. Pan, et al., “MFG-E8 Regulated by miR-99b-5p Protects Against Osteoarthritis by Targeting Chondrocyte Senescence and Macrophage Reprogramming via the NF-κB Pathway,” Cell Death & Disease 12, no. 6 (2021): 533.

[67] Q. He, D. Tian, Z. Wang, et al., “Modified Si Miao Powder Granules Alleviates Osteoarthritis Progression by Regulating M1/M2 Polarization of Macrophage Through NF-κB Signaling Pathway,” Frontiers in Pharmacology 21, no. 15 (2024): 1361561.

[68] C. Fang, R. Zhong, S. Lu, et al., “TREM2 Promotes Macrophage Polarization From M1 to M2 and Suppresses Osteoarthritis Through the NF-κB/CXCL3 Axis,” International Journal of Biological Sciences 20, no. 6 (2024): 1992–2007.

[69] Y. Shi, H. Tao, X. Li, et al., “κ-Opioid Receptor Activation Attenuates Osteoarthritis Synovitis by Regulating Macrophage Polarization Through the NF-κB Pathway,” Acta Biochimica et Biophysica Sinica 56, no. 1 (2024): 82–95.

[70] E. Giurisato, Q. Xu, S. Lonardi, et al., “Myeloid ERK5 Deficiency Suppresses Tumor Growth by Blocking Protumor Macrophage Polarization via STAT3 Inhibition,” Proceedings of the National Academy of Sciences of the United States of America 115, no. 12 (2018): E2801–E2810.

[71] M. Qian, S. Wang, X. Guo, et al., “Hypoxic Glioma-Derived Exosomes Deliver microRNA-1246 to Induce M2 Macro-Phage Polarization by Targeting TERF2IP via the STAT3 and NF-κB Pathways,” Oncogene 39, no. 2 (2020): 428–442.

[72] Z. Tian, F. Zeng, C. Zhao, and S. Dong, “Angelicin Alleviates Post-Trauma Osteoarthritis Progression by Regulating Macro-Phage Polarization via STAT3 Signaling Pathway,” Frontiers in Pharmacology 12 (2021): 669213.

[73] J. Bai, Y. Zhang, X. Zheng, et al., “LncRNA MM2P-Induced, Exosome-Mediated Transfer of Sox9 From Monocyte-Derived Cells Modulates Primary Chondrocytes,” Cell Death & Disease 11, no. 9 (2020): 763.

[74] N. Van Opdenbosch and M. Lamkanfi, “Caspases in Cell Death, Inflammation, and Disease,” Immunity 50, no. 6 (2019): 1352–1364.

[75] C. Pop and G. S. Salvesen, “Human Caspases: Activation, Specificity, and Regulation,” Journal of Biological Chemistry 284, no. 33 (2009): 21777–21781.

[76] G. S. Li, L. Cui, and G. D. Wang, “miR-155-5p Regulates Macro-Phage M1 Polarization and Apoptosis in the Synovial Fluid of Patients With Knee Osteoarthritis,” Experimental and Therapeutic Medicine 21, no. 1 (2020): 68.

[77] P. Luo, S. Peng, Y. Yan, P. Ji, and J. Xu, “IL-37 Inhibits M1-Like Macrophage Activation to Ameliorate Temporomandibular Joint Inflammation Through the NLRP3 Pathway,” Rheumatology 59, no. 10 (2020): 3070–3080.

[78] H. Wang, H. Zhang, K. Fan, et al., “Frugoside Delays Osteoarthritis Progression via Inhibiting miR-155-Modulated Synovial Macrophage M1 Polarisation,” Rheumatology (Oxford) 60, no. 10 (2021): 4899–4909.

[79] A. Kerschenmeyer, Ø. Arlov, V. Malheiro, et al., “Anti-Oxidant and Immune-Modulatory Properties of Sulfated Alginate Derivatives on Human Chondrocytes and Macrophages,” Biomaterials Science 5, no. 9 (2017): 1756–1765.

[80] J. Li, Y. Bi, H. Yang, and D. Wang, “Antioxidative Properties and Interconversion of Tert-Butylhydroquinone and Tert-Butylquinone in Soybean Oils,” Journal of Agricultural and Food Chemistry 65 (2017): 10598–10603.

[81] H. Zhang, J. Li, X. Xiang, et al., “Tert-Butylhydroquinone Attenuates Osteoarthritis by Protecting Chondrocytes and Inhibiting Macrophage Polarization,” Bone & Joint Research 10 (2021): 704–713.

[82] S. J. Wu, L. T. Ng, and C. C. Lin, “Antioxidant Activities of Some Common Ingredients of Traditional Chinese Medicine, Angelica Sinensis, Lyciumbarbarum and Poria Cocos,” Phytotherapy Research 18 (2004): 1008–1012.

[83] J. Qin, Y. S. Liu, J. Liu, et al., “Effect of Angelica Sinensis Polysaccharides on Osteoarthritis In Vivo and In Vitro: A Possible Mechanism to Promote Proteoglycans Synthesis,” Evidence-based Complementary and Alternative Medicine 2013 (2013): 794761.

[84] I. Lampronti, M. G. Manzione, G. Sacchetti, et al., “Differential Effects of Angelicin Analogues on NF-κB Activity and IL-8 Gene Expression in Cystic Fibrosis IB3-1 Cells,” Mediators of Inflammation 2017 (2017): 2389487.

[85] Y. Sun, K. Huang, L. Mo, et al., “Eucommia ulmoides Polysaccharides Attenuate Rabbit Osteoarthritis by Regulating the Function of Macrophages,” Frontiers in Pharmacology 12 (2021): 730557.

[86] C. X. Hu, K. Y. Hu, and J. F. Wang, “Potential Role of the Compound Eucommia Bone Tonic Granules in Patients With Osteoarthritis and Osteonecrosis: A Retrospective Study,” World Journal of Clinical Cases 8 (2020): 46–53.

[87] Z. Lv, X. Xu, Z. Sun, et al., “TRPV1 Alleviates Osteoarthritis by Inhibiting M1 Macrophage Polarization via Ca²⁺/CaMKII/Nrf2 Signaling Pathway,” Cell Death & Disease 12 (2021): 504.

[88] R. Uchiyama, E. Toyoda, M. Maehara, et al., “Effect of Platelet-Rich Plasma on M1/M2 Macrophage Polarization,” International Journal of Molecular Sciences 22, no. 5 (2021): 2336.

[89] L. Mazini, L. Rochette, B. Admou, S. Amal, and G. Malka, “Hopes and Limits of Adipose-Derived Stem Cells (ADSCs) and Mesenchymal Stem Cells (MSCs) in Wound Healing,” International Journal of Molecular Sciences 21 (2020): 1306.

[90] S. Cosenza, M. Ruiz, K. Toupet, C. Jorgensen, and D. Noel, “Mesenchymal Stem Cells Derived Exosomes and Microparticles Protect Cartilage and Bone From Degradation in Osteoarthritis,” Scientific Reports 7 (2017): 16214.

[91] C. H. Woo, H. K. Kim, G. Y. Jung, et al., “Small Extracellular Vesicles From Human Adipose-Derived Stem Cells Attenuate Cartilage Degeneration,” Journal of Extracellular Vesicles 9 (2020): 1735249.

[92] S. Tang, P. Chen, H. Zhang, et al., “Comparison of Curative Effect of Human Umbilical Cord-Derived Mesenchymal Stem Cells and Their Small Extracellular Vesicles in Treating Osteoarthritis,” International Journal of Nanomedicine 16 (2021): 8185–8202.

[93] L. Gui-Shi, C. Lei, and W. Guang-Da, “miR-155-5p Regulates Macrophage M1 Polarization and Apoptosis in the Synovial Fluid of Patients With Knee Osteoarthritis,” Experimental and Therapeutic Medicine 21, no. 1 (2021): 68.

[94] P. T. L Hong, H. J. Kim, W. K. Kim, and J. H. Nam, “Flos Magnoliae Constituent Fargesin Has an Anti-Allergic Effect via ORAI1 Channel Inhibition,” Korean Journal of Physiology & Pharmacology 25 (2021): 251–258.

[95] S. Pal and V. B. Konkimalla, “Sulforaphane Regulates Phenotypic and Functional Switching of Both Induced and Spontaneouslydifferentiating Human Monocytes,” International Immunopharmacology 35 (2016): 85–98.

[96] V. Byles, A. J. Covarrubias, I. Ben-Sahra, et al., “The TSC-mTOR Pathway Regulates Macrophage Polarization,” Nature Communications 4 (2013): 2834.

[97] J. W. Xie, Y. Wang, K. Xiao, et al., “Alpha Defensin-1 Attenuates Surgically Induced Osteoarthritis in Association With Promoting M1 to M2 Macrophage Polarization,” Osteoarthritis and Cartilage 29, no. 7 (2021): 1048–1059.

[98] S. J. Van Dyken and R. M. Locksley, “Interleukin-4 and Interleukin-13 Mediated Alternatively Activated Macrophages: Roles in Homeostasis and Disease,” Annual Review of Immunology 31 (2013): 317–343.

[99] J. Jiang, T. Jia, W. Gong, B. Ning, P. H. Wooley, and S. Y. Yang, “Macrophage Polarization in IL-10 Treatment of Particle-Induced Inflammation and Osteolysis,” American Journal of Pathology 186, no. 1 (2016): 57–66.

[100] K. Li, G. Yan, H. Huang, et al., “Anti-Inflammatory and Immunomodulatory Effects of the Extracellular Vesicles Derived From Human Umbilical Cord Mesenchymal Stem Cells on Osteoarthritis via M2 Macrophages,” Journal of Nanobiotechnology 20, no. 38 (2022): 38.

[101] L. Hyeonyoul, K. Heungdeok, S. Jinwon, et al., “Tissue Gene-C Promotes an Anti-Inflammatory Micro-Environment in a Rat Monoiodoacetate Model of Osteoarthritis via Polarization of M2 Macrophages Leading to Pain Relief and Structural Improvement,” Inflammopharmacology 28, no. 5 (2020): 1237–1252.

[102] C. Manferdini, F. Paolella, E. Gabusi, et al., “Adipose Stromal Cells Mediated Switching of the Pro-Inflammatory Profile of M1-Like Macrophages Is Facilitated by PGE2: In Vitro Evaluation,” Osteoarthritis and Cartilage 25, no. 7 (2017): 1161–1171.

[103] F. Zhou, J. Mei, S. Yang, et al., “Modified ZIF-8 Nanoparticles Attenuate Osteoarthritis by Reprogramming the Metabolic Pathway of Synovial Macrophages,” ACS Applied Materials & Interfaces 12, no. 2 (2020): 2009–2022.

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