Hamza Malick

Introduction: Osteoarthritis (OA) is an autoimmune disorder characterized by the degradation of cartilage and chronic inflammation at the synovium. It is considered to be one of the most prevalent causes of morbidity and disability in individuals over 40, with treatment currently limited to NSAID’s, steroids, and other symptomatic relief.^1,3 It is believed that OA is caused by an imbalanced expression of pro-inflammatory biomarkers and an overwhelming polarization of macrophages into an M1 phenotype.² Previous studies have established the presence of M1 macrophages as pro-apoptotic and pro-inflammatory. M1 macrophages are also heavily linked to the recruitment of neutrophiles releasing inflammatory cytokines and matrix metalloproteases (MMPs) in inflammatory settings which is correlatively linked to the severity and degree of progression in OA.^1,5 Previous studies have alluded to the polarization of macrophages from the pre-dominant M1 phenotype to an M2 (anti-inflammatory) phenotype to be an important basis for future treatment in OA.^2,8 Recent studies reported that extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) promote macrophage polarization into the M2 phenotype and consequently create chondrogenic environments^2,6,8 This supports the potential use of MSC-derived EVs (MSC-EVs) for the treatment of OA. Methods: To first establish the correlation between M1 macrophages and OA, patient synovial fluid samples were tested for M1 macrophage biomarkers as well as inflammatory cytokines and MMP’s. This was analyzed alongside clinical assessments of disease severity and progression.⁵ MSC-derived EVs were then treated in an OA mouse model as well as chondrocytes isolated from synovial fluid of OA mice. To determine the role of microRNA-223 (miR-223) in MSC-EVs, miR-223 inhibitors were co-administered. Histological analysis was used to examine cartilage deposition post-treatment. RT-PCR and flow cytometry were also used to examine the levels of M1 and M2 macrophages in vivo and in cultures upon EV treatment.⁷ Results: The clinical study showed a positive correlation between the severity and clinical grade of OA in patients and the amount of M1 macrophages and MMPs present within the synovial fluid of the patients.⁵ Furthermore, OA mice treated with EVs containing miRNA-223 displayed a greater degree of cartilage deposition in the synovium than their counterparts treated with vehicle control or EVs along with miRNA-223 inhibitors.^2,7 The cultures of chondrocytes in synovial fluid also showed a massive shift in polarity from M1 macrophages towards M2 macrophages upon EV treatment. ^2,7,6 Consistent with these findings, the treatment of MSC-derived EVs in OA patients showed a positive correlation towards the polarization of macrophages from an M1 into an M2 phenotype and improvements in chondrocyte survival and cartilage deposition. Conclusion: MSC-EVs have therapeutic effects in OA by promoting the M2 macrophage polarization and MiRNA-223 was one of major factors responsible for the EV-mediated M2 polarization in OA.

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2. Zhao X, Zhao Y, Sun X, Xing Y, Wang X, Yang Q. Immunomodulation of MSCs and MSC-Derived Extracellular Vesicles in Osteoarthritis. Front Bioeng Biotechnol. 2020;8:575057. Published 2020 Oct 29. doi:10.3389/fbioe.2020.575057
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5. 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. Published 2019 Jun 13. doi:10.1186/s13075-019-1923-x
6. Heo JS, Choi Y, Kim HO. Adipose-Derived Mesenchymal Stem Cells Promote M2 Macrophage Phenotype through Exosomes. Stem Cells Int. 2019;2019:7921760. Published 2019 Nov 5. doi:10.1155/2019/7921760
7. Lu FB, Chen DZ, Chen L, et al. Attenuation of Experimental Autoimmune Hepatitis in Mice with Bone Mesenchymal Stem Cell-Derived Exosomes Carrying MicroRNA-223-3p. Mol Cells. 2019;42(12):906-918. doi:10.14348/molcells.2019.2283
8. He X, Dong Z, Cao Y, et al. MSC-Derived Exosome Promotes M2 Polarization and Enhances Cutaneous Wound Healing. Stem Cells Int. 2019;2019:7132708. Published 2019 Sep 9. doi:10.1155/2019/7132708