MicroRNA-128a represses chondrocyte autophagy and exacerbates knee osteoarthritis by disrupting Atg12

Wei-Shiung Lian,Yu-Shan Chen,Yi-Chih Sun,Shin-Long Wu,Re-Weng Wu,Lin-Hsiu Weng,Jih-Yang Ko,Feng-Sheng Wang,Holger Jahr

doi:10.1038/s41419-018-0994-y

Abstract

Chondrocyte loss is a prominent feature of osteoarthritis (OA). Autophagy is indispensable in maintaining the metabolic activities of cells exposed to deleterious stress. The contribution of microRNA signaling to chondrocyte autophagy in OA development remains elusive. We uncovered an association between poor autophagy and increased miR-128a expressions in articular chondrocytes of patients with end-stage knee OA and in a rat anterior cruciate ligament transection (ACLT) model for OA development. Cartilage matrix degradation and severe OA histopathology was evident upon forced miR-128a expression within the articular compartment. Intra-articular injections with miR-128a antisense oligonucleotide stabilized chondrocyte autophagy and slowed ACLT-mediated articular tissue destruction, including cartilage erosion, synovitis, osteophyte formation, and subchondral plate damage. In vitro, miR-128 signaling hindered Atg12 expression, LC3-II conversion, and autophagic puncta formation through targeting the 3′-untranslated region of Atg12. It increased apoptotic programs, diminishing cartilage formation capacity of articular chondrocytes. Inactivating histone methyltransferase EZH2 reduced methyl histone H3K27 enrichment in the miR-128a promoter and upregulated miR-128a transcription in inflamed chondrocytes. Taken together, miR-128a-induced Atg12 loss repressed chondrocyte autophagy to aggravate OA progression. EZH2 inactivation caused H3K27 hypomethylation to accelerate miR-128a actions. Interruption of miR-128a signaling attenuated chondrocyte dysfunction and delayed OA development. Our data provide new insights into how miR-128a signaling affects chondrocyte survival and articular cartilage anabolism and highlight the potential of miR-128a targeting therapy to alleviate knee OA.

Highlights

Osteoarthritis (OA) is the most common cause of joint abnormality, accounts for disability in the elderly and is a huge socioeconomic burden around the world[1]
Affected rat joints displayed an altered articular cartilage morphology, like microstructural erosion and matrix loss as evident from faint histochemical Safranin-O staining. Consistent with these substantial histopathological changes, anterior cruciate ligament transection (ACLT)-affected articular compartments further showed a significant increase in Mankin score and OARSI score as compared to the sham group (Fig. 1a)
Chondrocytes in the ACLT-injured joints revealed weak LC3 and Atg[12] immunostaining (Fig. 1d), which is indicative of defective autophagy in these cells

Summary

Introduction

Osteoarthritis (OA) is the most common cause of joint abnormality, accounts for disability in the elderly and is a huge socioeconomic burden around the world[1]. This disease progressively devastates the entire articular joint. Official journal of the Cell Death Differentiation Association. Lian et al Cell Death and Disease (2018)9:919. Autophagy integrates skeletal morphogenesis[7] and cartilage tissue homeostasis[8]. While the etiological cause of OA remains inconclusive, accumulating evidence hints towards an association between aberrant autophagy in articular chondrocytes and the development of OA9,10. Cartilagespecific loss of autophagy repressor mTOR sustains chondrocyte autophagy and prevents aging-induced OA12, while Rapamycin activation of autophagy reduces glucocorticoid-mediated chondrocyte apoptosis in OA cartilage[13]

Methods

Results

Conclusion