miR-140 Attenuates the Progression of Early-Stage Osteoarthritis by Retarding Chondrocyte Senescence

Abstract

Osteoarthritis (OA) is a major cause of joint pain and disability, and chondrocyte senescence is a key pathological process in OA and may be a target of new therapeutics. MicroRNA-140 (miR-140) plays a protective role in OA, but little is known about its epigenetic effect on chondrocyte senescence. In this study, we first validated the features of chondrocyte senescence characterized by increased cell cycle arrest in the G0/G1 phase and the expression of senescence-associated β-galactosidase (SA-βGal), p16INK4a, p21, p53, and γH2AX in human knee OA. Then, we revealed in interleukin 1β (IL-1β)-induced OA chondrocytes in vitro that pretransfection with miR-140 effectively inhibited the expression of SA-βGal, p16INK4a, p21, p53, and γH2AX. Furthermore, in vivo results from trauma-induced early-stage OA rats showed that intra-articularly injected miR-140 could rapidly reach the chondrocyte cytoplasm and induce molecular changes similar to the in vitro results, resulting in a noticeable alleviation of OA progression. Finally, bioinformatics analysis predicted the potential targets of miR-140 and a mechanistic network by which miR-140 regulates chondrocyte senescence. Collectively, miR-140 can effectively attenuate the progression of early-stage OA by retarding chondrocyte senescence, contributing new evidence of the involvement of miR-mediated epigenetic regulation of chondrocyte senescence in OA pathogenesis.

Recent progress on the role of miR-140 in cartilage matrix remodelling and its implications for osteoarthritis treatment

“…Therapeutic interventions such as direct articular injection of miR-140 could influence the biological behaviour of synovial blasts and the subsequent inflammatory response of OA. Moreover, miR-140 attenuates the progression of early-stage OA by slowing chondrocyte senescence [49].…”

“…Additionally, the inhibitory effect of miR-140-5p in chondrocyte hypertrophy has been shown through targeting histone deacetylase (HDAC)-4 [ 48 ] and SMAD1 [ 47 ]. During the inhibition of chondrocyte senescence, miR-140-5p targets Jagged1 (JAG1) and NUMB-like endocytic adaptor protein (NUMBL) in the Notch pathway and insulin-like growth factor 1 receptor (IGF1R) and TLR4 in the phosphatidylinositol 3′-kinase (PI3K)-AKT pathway [ 49 ]. Moreover, miR-140-5p inhibits cartilage matrix degradation through targets including MMP-13, ADAMTS-5, and insulin-like growth factor-binding protein (IGFBP)-5 [ 37 ].…”

Therapeutic effect and mechanisms of intra-articular injections of microRNA-140-5p on early-stage osteoarthritis in rats

“…Although the central role of cartilage degeneration in OA has been recognized, OA is a total joint disease, while not just a dysfunction of cartilage [12]. Although we found in this study that the intraarticularly injected miR-140-5p has no extra-articular distribution, it is substantially uptaken by the intra-articular non-cartilage tissues such as synovium and meniscus.…”

“…The sections were dewaxed and hydrated before being stained with haematoxylin & eosin (HE) and toluidine blue. The chondrocyte numbers in an equal area and the cartilage thickness were measured as reported previously [12], and the severity of the cartilage lesions was graded using the modified Mankin score. All sections were assessed independently by three blinded assessors (SHB, YTM and CY), and the final results were determined via a consensus.…”

High-Throughput Identification of MiR-145 Targets in Human Articular Chondrocytes

“…A growing number of studies have associated changes in the expression of dozens of miRNAs to the development of OA [67]. Well studied examples include protective miR-140 [68] or detrimental miR-138 [69]. Moreover, miRNAs have also been proposed as biomarkers of the disease [67] that could facilitate early OA detection.…”