Ls, even though not broadly studied, are also believed to take part in the regulation of OA development [73]. Zeng et al. identified that long non-coding RNA (lncRNA) prostate cancer gene expression marker 1 (PCGEM1) was Delta-like 3 (DLL3) Proteins Biological Activity overexpressed in exosomes from OA fibroblast-like synoviocytes (FLSs). FLS-derived exosomal PCGEM1 aggravated IL-1-caused apoptosis and cartilage matrix degeneration in chondrocytes by sponging miR-142-5p and upregulating RUNX2 [49]. FLSderived exosomal lncRNA H19 enhanced cell migration and proliferation, inhibited matrix degradation also as alleviated OA progression by suppressing the miR-106b-5p/TIMP2 axis [74]. Although cytokines made by macrophages along with the imbalance involving M1 and M2 macrophages are essential in OA pathogenesis, the effects of macrophage-derived exosomes on OA have been seldom studied therefore far [75]. two.two.four. Exosomes Derived from Osteoblasts and osteocytes The remodeling of subchondral bone is a essential function of OA and strongly linked with disease severity and joint discomfort in clinical OA sufferers [76]. Altered crosstalk amongst articular cartilage and also the subchondral bone, which is usually modulated by exosomes in OA progression, has attracted a lot interest but not been properly studied. Wu et al. discovered that exosomes developed by osteoblasts in osteoarthritic, sclerotic subchondral bone contained a higher degree of miR-210-5p, which decreased the rate of oxygen consumption by chondrocytes, altered their bioenergetic state, and accelerated the progression of cartilage degeneration [32]. Exosome-like EVs happen to be extracted from osteoblasts harvested from OA subchondral bones. The OA osteoblast-derived exosomes have been identified to have up-Bioengineering 2022, 9,ten ofregulated expression of five miRNAs–hsa-miR-885-3p, hsamiR-4717-5p, hsamiR-210-5p, hsa-miR-135a-3p, and hsa-miR-1225-5p–than these obtained from the healthy controls; the physiological and pathological roles of these molecules still stay unclear [19]. Osteocytes release miRNA-containing exosomes, which provide their components via blood circulation to the recipient cells to regulate biological processes [77]. Moreover, osteocytes are sensitive to mechanical strains. Cultured below cyclic stretch of 8 shape variable at a frequency of 0.1 Hz for 30 min, osteocytes create exosomes containing differentially expressed miRNAs compared with these from non-loading groups. These exosomes promoted the proliferation and osteogenesis of human PDLSCs by activating the miR-181b-5p/PTEN/AKT signaling pathway [78]. Myostatin, a myokine secreted by muscles, suppressed the expression of miR-218 in osteocyte-derived exosomes. Treated with these exosomes, osteoblasts showed decreased osteoblastic differentiation and downregulated AKT Serine/Threonine Kinase 3 (AKT3) Proteins Source activity in the Wnt signaling pathway [79]. Osteocyte exosomes had been also discovered to accelerate benign prostatic hyperplasia improvement by promoting cell proliferation [80]. 2.2.5. Exosomes Derived from Adipose Tissue IPFP is intraarticular adipose tissue that functions to lessen mechanical loading and absorb shock, and act as an abundant supply of cytokines, lipid mediators at the same time as regenerative cells for cartilage repair [81]. IPFP is mainly comprised of adipocytes, along with other cell sorts, including IPFP-derived MSCs and immune cells, are also found. As discussed earlier, intense interest has been spurred in IPFP-derived MSCs and IPFPExos [65]. Given the regulatory roles of adipose tissue in immune and nonimmune functions, compositional an.