Table 2.

The therapeutic effects and underlying mechanisms of exosomes derived from stem cells on OA

Exosomes	Separation method	Mechanisms of actions	Biological effects
BMSCs- derived exosomes	Ultracentrifugation and Ultrafiltration	• Prevent OA chondrocytes from apoptosis by p38, ERK, and akt signaling pathways.182,183 • Regulate catabolism and anabolism in chondrocytes.182 • Maintain mitochondrial membrane potential and inhibit mitochondrial dysfunction.183,184 • Suppress osteoclast activity in subchondral bone via RANKL-RANK-TRAF6 pathway.185 • Inhibit proliferation and enhance apoptosis in synovial fibroblasts via microRNA-26a-5p/ PTGS2 pathway.186	• Reduce the damage of articular cartilage.182,185 • Abrogate the degradation of subchondral bone.182,185 • Inhibit aberrant nerve invasion and abnormal formation of H-type vessel in subchondral bone.185 • Relieve pain in OA model.185 • Decrease the infiltration of inflammatory cells, down-regulate the level of inflammatory factor and alleviate pathological changes of synovium.186 • Inhibit the activation of macrophages.182
EMSCs- derived exosomes	Immunoaffinity purification and Ultracentrifugation	• Promote M2 macrophages infiltration, decrease M1 macrophages and proinflammatory cytokine production.218 • Activate adenosine-dependent AKT and ERK signaling pathways by exosomal CD73.218 • Reverse IL-1β-mediated inhibition of s-GAG synthesis and weaken the nitric oxide and MMP13 production via adenosine-mediated activation of AKT, ERK and AMPK.220 • Enhance miR-135b expression and decrease Sp1 expression.221	• Repair the damage of cartilage and subchondral bone.217,220,221 • Enhance surface regularity and integration with adjacent host cartilage.218 • Promote chondrogenic formation.218 • Regulate the migration, proliferation and matrix synthesis of chondrocytes.218 • Prevent from cartilage destruction and matrix degradation.219 • Suppress inflammation and restore matrix homeostasis.220
AMSCs- derived exosomes	Ultracentrifugation and Ultrafiltration	• Inhibit the activity of senescence-associated β-Galactosidase and γH2AX foci accumulation, reduced IL-6 and PGE2 levels, enhanced the release of IL-10.208 • Restrain the production of proinflammatory mediators TNF-α, IL-6, PGE2 and NO, and reduce the MMPs activity and MMP-13 expression, enhance the levels of the IL-10 and Collagen-II.209 • Promote chondrocytes viability, maintain the balance of anabolism and catabolism via miR-100-5p-mediated mTOR inhibition and autophagy enhancement.146 • Enhance proliferation and chondrogenic potential of periosteal cells via upregulating miR‑145 and miR‑221211	• Down-regulate mitochondrial membrane potential.208 • promote chondrogenesis in periosteal cells and increase chondrogenic markers211 • Show the potential anti-inflammatory and chondro-protective effects.208,209 • Ameliorate the pathological severity of articular cartilage and partially improve the abnormal gait.146
SMSCs- derived exosomes	Ultrafiltration	• Promote the proliferation and migration of chondrocytes via activation of YAP, prevent the ECM from damage through miR-140-5p/RalA-mediated increase of SOX9 and Aggrecan in vitro.122,200 • Reverse GC-induced proliferation inhibition and apoptosis of BMSCs.201	• Promote cartilage regeneration, Maintain the content of collagen II and attenuate OA progression.122,195,200 • Decrease the glucocorticoid (GC)-induced trabecular bones loss, bone marrow necrosis and fatty cells accumulation, improve the bone mineral density and the microstructures of the trabecular bone.201
AFSCs- derived exosomes	Precipitation	• Inhibit M1 polarization, decrease the expression of CD86, iNOS and IL-1 R1, regulate immunosuppressive and chondrogenesis via exosomal TGFβ and IDO.222	• Enhance pain tolerance level and induce an almost complete restoration of hyaline cartilage with good surface regularity.222
SHEDs- derived exosomes	Ultracentrifugation	• Inhibit miR-100-5p-mediated mTOR expression.224	• Inhibit inflammatory reaction and maintain anabolism homeostasis of chondrocytes.224
iMSCs- derived exosomes	Ultrafiltration	• Promote chondrocytes migration and proliferation.200	• Decrease the OARSI in experimental OA model, present a potent therapeutic effect on OA.200