Aniruth Srinivasaraghavan

Introduction: Osteoarthritis (OA) is the irreversible degeneration and dysfunction of articular cartilage and adjacent tissues that eventually leads to joint destructions^1,2. Non-pharmacological treatment such as exercise, weight loss, as walking aids as indicated are recommended for first line of treatment. Exercise therapy is recommended for helping to decrease pain and improve joint mobility³. Joint replacement surgery can be indicated or end stage osteoarthritis. It is only cost effective for patients with severely affected functional status³. Mesenchymal stem cells (MSCs) are being studied source of cells for engineering cartilage in the treatment of degenerative bone diseases due to their self-renewal capacity, accessibility, and multilineage differentiation capacity^2,3. After reaching the damaged tissue site, BMSCs perform wound healing of damaged tissues through either a paracrine mechanism or directed differentiation^5,6. One way in which MSCs can be applied in therapeutic setting is through their paracrine regulation of macrophagic cells for the treatment of OA. Methods: OA was induced in mice with tuberous sclerosis complex 1 or Rheb deletion specifically in the myeloid lineage. M1 or M2-polarised macrophages in synovial tissues of patients with OA and OA mice were analyzed⁵. In rats with rotator cuff reconstruction, BMSC-Exos were injected into the tail vein to analyze the rotator cuff tendon-bone interface healing⁶. Mouse ADSCs were isolated and cultured and during the last 6–8 weeks of HFD feeding, mice were intraperitoneally administrated with ADSC-derived exosomes⁷. hBM-MSCs were adhered to the plastic culture disk and an exosome was utilized as a nanocarrier for delivering miR-181b⁸. Results: Hyperactive mTORC1 in synovial macrophages enforced cartilage degeneration in TSC1KO mice through M1 polarization. In contrast, macrophage mTORC1 inactivation enhanced M2 polarization and attenuated OA⁵. It was found that BMSC-Exos significantly reduced the serum levels of TNF-α, IL-1β, IL-6, and IL-8 in rats at all time points. The flow cytometry results show that the expression of CD86, a surface marker of M1 macrophages⁶. exosomes from ADSCs transferred into macrophages to induce anti-inflammatory M2 phenotypes through the transactivation of arginase-1 by exosome-carried active STAT3⁷. M1 phenotype was high in the porous titanium (PT) group but significantly reduced treated with Exo-181b. CD206, the marker of M2 polarization, has low positive percentage in the PT group but significantly increased with the treatment of Exo-181b⁸. Conclusion: MSC exosomes have anti-inflammatory effects through the downregulation M1 polarization and promotion of M2 differentiation in order to enhance tissue regeneration

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