MiR-582-3p alleviates osteoarthritis progression by targeting YAP1

Highlights

• YAP1 is upregulated in OA chondrocytes from rats.

• MiR-582-3p alleviates regulates cell apoptosis, inflammatory responses and ECM homeostasis in OA rat chondrocytes and C28/I2 cells.

• MiR-582-3p can bind with the 3′UTR of YAP1.

• YAP1 reverses miR-582-3p-mediated cell apoptosis, inflammatory responses and ECM homeostasis in OA rat chondrocytes and C28/I2 cells.

• MiR-582-3p suppresses OA development via targeting YAP1 in vivo.

Abstract

Osteoarthritis (OA) is a widespread degenerative joint disease that affects more than 350 million people worldwide. Although YAP1 has been proved to play a key role in OA, the biological function and mechanism of YAP1 in OA still need further investigation. In the present study, we demonstrated that YAP1 was highly expressed in OA rat chondrocytes. Recently, growing microRNAs (miRNAs) have been reported to play important roles in OA development. Among them, miR-582-3p is one of the few significantly downregulated miRNAs and attracted our attention. Functional investigations indicated that miR-582-3p inhibited chondrocyte apoptosis, reduced the proinflammatory cytokine production and suppressed extracellular matrix (ECM) degradation. Subsequently, molecular mechanism exploration implied that YAP1 is a downstream target of miR-582-3p. Furthermore, rescue assays revealed that YAP1 amplification can reverse miR-582-3p mimic-mediated effects on chondrocyte apoptosis, inflammatory response, and ECM degradation. Moreover, the OA rat model was established to explore the function of miR-582-3p/YAP1 axis in vivo. The results showed that YAP1 overexpression can recover the effects induced by injection of AAV-miR-582-3p mimic on OA progression. To sum up, these findings implied a crucial role of miR-582-3p/YAP1 axis in OA, which may provide a promising therapeutic strategy for OA.

Introduction

Osteoarthritis (OA) is one of the most common degenerative joint diseases, characterized by the deterioration of cartilage, synovial inflammation and decreased cartilage cellularity (Hussain et al., 2016). The incidence of OA increases with age and it has become a primary cause of pain or disablement (Pereira et al., 2016). At present, the therapeutic options for OA are mainly aimed at symptom control and pain relief. However, no treatment has been reported to be effective for modulating the development of OA yet (Taylor, 2018). To improve the therapeutic options for OA patients, it is necessary to investigate the pathogenesis of OA.

Yes‐associated protein 1 (YAP1) is a main component of the Hippo/YAP1 signaling pathway and closely associated with the cell differentiation of skeletal lineage and the development of bone (Pan, 2010; Yang et al., 2019; B. Zhao et al., 2010). Plenty of studies have validated that YAP1 participates in various of diseases. For example, YAP1 is upregulated in Acute Pancreatitis cells and facilitates Acute Pancreatitis progression (Gu et al., 2019b). Early alteration of YAP1 can accelerate Alzheimer’s disease progression (Xu et al., 2018). YAP1 exerts promotive effects on the proliferation of diabetic retinopathy by regulating the MALAT1/miR-200b-3p/VEGFA axis (Han et al., 2019). Notably, recent researches indicated that YAP1 regulates chondrocyte proliferation in multiple diseases. For instance, YAP1 promotes early chondrocyte proliferation by regulating SOX6 expression during skeletal development and bone regeneration (Deng et al., 2016). YAP1 enhances chondrocyte proliferation by activating the β-catenin signaling pathway (Yang et al., 2017). Besides, a recent study revealed that overexpression of YAP1 can inhibit ATDC5 chondrogenic cell proliferation through interacting with Beclin-1 in OA progression (Zhang et al., 2019). However, the underlying mechanism of YAP1 in OA development still needs further elucidation.

Mechanistically, it is well known that microRNAs (miRNAs) are capable of inducing gene silencing by combining with mRNAs, and then participate in multiple diseases, including OA. For instance, miR-128 suppresses osteoporosis development by targeting SIRT6 (J. Zhao et al., 2019). Knockdown of miR-195-5p inhibits osteoarthritis progression through targeting REGγ (Shu et al., 2019). Therefore, the miRNA-mRNA network has significant means in the progression of various diseases. However, little is known about the regulatory mechanism of miR-582-3p in OA up till now.

In the current study, we focused on the function and regulatory mechanism of miR-582-3p in modulating chondrocyte proliferation, inflammatory response and ECM homeostasis. Our results may indicate miR-582-3p as a novel target for improving OA therapy.