Synovial Mesenchymal Stem Cell-Derived EV-Packaged miR-31 Downregulates Histone Demethylase KDM2A to Prevent Knee Osteoarthritis

Abstract

Extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) have emerged as important mediators of intercellular communication in response to cartilage damage. In this study, we sought to characterize the inhibitory role of microRNA (miR)-31 encapsulated in synovial MSC (SMSC)-derived EVs in knee osteoarthritis (OA). The expression of miR-31, lysine demethylase 2A (KDM2A), E2F transcription factor 1 (E2F1), and pituitary tumor transforming gene 1 (PTTG1) was validated in cartilage tissues of knee OA patients. Following SMSC-EV extraction and identification, chondrocytes with the miR-31 inhibitor were added with SMSC-EVs, whereupon the effects of miR-31 on proliferation and migration of chondrocytes were assessed. The interaction among miR-31, KDM2A, E2F1, and PTTG1 in chondrocyte activities was probed in vitro , along with an in vivo mouse knee OA model. We identified downregulated miR-31, E2F1, and PTTG1 and upregulated KDM2A in cartilage tissues of knee OA patients. SMSC-EV-packaged miR-31 potentiated chondrocyte proliferation and migration as well as cartilage formation by targeting KDM2A. Mechanistically, KDM2A bound to the transcription factor E2F1 and inhibited its transcriptional activity. Enrichment of E2F1 in the PTTG1 promoter region activated PTTG1 transcription, accelerating chondrocyte proliferation and migration. SMSC-EVs and EVs from miR-31-overexpressed SMSCs alleviated cartilage damage and inflammation in knee joints in vivo . SMSC-EV-encapsulated miR-31 ameliorates knee OA via the KDM2A/E2F1/PTTG1 axis.

Histone Modifications and Chondrocyte Fate: Regulation and Therapeutic Implications

“…A recent study shows that synovial MSC (SMSC)derived, extracellular vesicle (EV)-packaged miR-31 potentiates chondrocyte proliferation and migration as well as cartilage formation by targeting KDM2A, which binds to the transcription factor E2F1 and inhibits its transcriptional activity. SMSC-EVs and EVs from miR-31-overexpressed SMSCs alleviates cartilage damage and inflammation in a mouse OA model (Wang et al, 2020). These findings indicate that microRNA based epigenetic regulation and histone demethylation may interact to regulate inflammatory responses and chondrocyte ECM production during OA, and provide a novel approach for the design of effective OA therapeutics.…”

Exosomes Derived from Non-Classic Sources for Treatment of Post-Traumatic Osteoarthritis and Cartilage Injury of the Knee: In Vivo Review

“…A total of 161 studies were obtained from the initial query search. After evaluating these reports, their reference lists, and using additional search terms, a total of 12 studies met the criteria for analysis described previously ( Figure 1 ) [ 11 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ]. The exosomes in these 12 studies were derived from various sources, as listed in Table 1 .…”

“…Likewise, in a more recent study by Wang et al, EVs from SMSCs were packaged with microRNA (miR)-31 (SMSC-EV-miR-31), which has been shown to promote the growth and migration of chondrocytes [ 22 , 35 ]. As the authors had hypothesized, the OARSI score, degree of cartilage destruction seen on tissue sections, and levels of IL-1β, IL-6, and TNF-α were significantly decreased in OA mice treated with SMSC-EV-miR-31 compared to OA mice without treatment [ 22 ]. Therefore, SMSC-EVs-miR-31 may reduce knee articular cartilage damage and joint inflammation, similar to SMSC-140-Exos [ 22 ].…”

“…As the authors had hypothesized, the OARSI score, degree of cartilage destruction seen on tissue sections, and levels of IL-1β, IL-6, and TNF-α were significantly decreased in OA mice treated with SMSC-EV-miR-31 compared to OA mice without treatment [ 22 ]. Therefore, SMSC-EVs-miR-31 may reduce knee articular cartilage damage and joint inflammation, similar to SMSC-140-Exos [ 22 ].…”

Is Extracellular Vesicle-Based Therapy the Next Answer for Cartilage Regeneration?

“…Respectively, human BMMSCs and human SMMSCs overexpressing miR-26a-5p and miR-31 secrete EVs enriched in these miRNAs. These EVs alleviate cartilage destruction, matrix degradation, and inflammation in OA models based on knee joint instability induced by surgery, in the rat for EVs carrying miR-26a-5p according to the authors' subjective scores based on synovitis inflammation, synovial thickening, and subchondral bone erosion (Jin et al, 2020) and in the mouse for EVs carrying miR-31 according to OARSI scores (Wang et al, 2020). EVs derived from rat BMMSCs transfected to overexpress miR-135b favor rat chondrocyte proliferation in vitro (Wang et al, 2018).…”