Exosomes Derived from M2 Macrophages Exert a Therapeutic Effect via Inhibition of the PI3K/AKT/mTOR Pathway in Rats with Knee Osteoarthritic

Abstract

Macrophages are commonly classified as M1 macrophages or M2 macrophages. M2 macrophages are obtained by stimulation of IL-4 with anti-inflammatory and tissue repair effects. Exosomes are 30–150 nm lipid bilayer membrane vesicles derived from most living cells and have a variety of biological functions. Previous studies have shown that macrophage exosomes can influence the course of some autoimmune diseases, but their effect on knee osteoarthritis (KOA) has not been reported. Here, we analyze the roles of exosomes derived from M2 macrophage phenotypes in KOA rats. Exosomes were isolated from the supernatant of M2 macrophages and identified via transmission electron microscopy (TEM), Western blotting, and DLS. The results showed that M2 macrophage exosomes significantly attenuated the inflammatory response and pathological damage of articular cartilage in KOA rats. In addition, a key protein associated with KOA including Aggrecan, Col-10, SOX6, and Runx2 was significantly increased, while MMP-13 was significantly suppressed following treatment with M2 macrophage exosomes. The present study indicated that M2 macrophage exosomes exerted protective effects on KOA rats mainly mediated by the PI3K/AKT/mTOR signal pathway. These findings provide a novel approach for the treatment of KOA.

Macrophage‐derived extracellular vesicles regulate follicular activation and improve ovarian function in old mice by modulating local environment

“…50 EVs derived from M2 Mφs were also reported to have a therapeutic effect in a rat knee osteoarthritic model or in glioma through inhibition of the PI3K/mTOR signalling pathway. 51,52 Consistent with the results of these studies, our results further demonstrated the differential regulation of primordial follicle activation by polarised Mφs through their derived EVs and the shuttling of specific miRNAs.…”

Macrophage-Derived Small Extracellular Vesicles in Multiple Diseases: Biogenesis, Function, and Therapeutic Applications

“…PI3K/AKT, as a classical anti-apoptotic pathway, can combat cartilage apoptosis in osteoarthritis by regulating multiple downstream pathways. Studies have confirmed that M2-sEV intervention reduces the expression of PI3K/Akt/mTOR in KOA model rats (Da-Wa et al, 2021). After tendon injury (TI), the natural tendon structure cannot be reestablished, and fibrosis limits normal physiological function.…”

“…High expression of cirRNA-EP400 in M2-sEVs promotes FGF1/7/9 expression in fibroblasts and tendinocytes by inhibiting miRNA-15b-5p. The expressions of COL-I, COL-III, α-SMA, and TGF-β1 in tendinocytes and fibroblasts increase to promote fibrosis, proliferation, and migration of fibroblasts and tendinocytes after TI and ultimately promote perineural fibrosis after tendon injury ( Da-Wa et al, 2021 ). In addition to this pathway, M-sEVs can also directly target the expression of Smad7 by secreting miRNA-21-5p, activating the TGF-β1 pathway in the tendon, and inducing perineural fibrosis after TI ( Cui et al, 2019 ).…”

MSC-EV therapy for bone/cartilage diseases

“…They successfully treated collagen-induced arthritis by direct binding of these targeted liposomes to synovial fibroblast like cells ( Vanniasinghe et al, 2014 ). Moreover, several studies took advantage of immune cell-derived EVs to efficiently target inflammatory joints, such as EVs derived from M2 macrophages ( Da-wa et al, 2021 ), neutrophils ( Zhang et al, 2022 ; Headland et al, 2015 ), and dendritic cell ( Lee et al, 2021 ).…”