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miR-146a facilitates osteoarthritis by regulating cartilage homeostasis via targeting Camk2d and Ppp3r2
Xudong Zhang1, Chuandong Wang2, Jingyu Zhao1
1The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Abstract:
Osteoarthritis (OA), characterized by insufficient extracellular matrix synthesis and cartilage degeneration, is known as an incurable disease because its pathogenesis is poorly elucidated. Thus far, limited information is available regarding the pathophysiological role of microRNAs (miRNAs) in OA. In this study, we investigated the specific function of miR-146a in OA pathophysiology using mouse OA models. We found that the articular cartilage degeneration of miR-146a knockout (KO) mice was alleviated compared with that of the wild-type (WT) mice in spontaneous and instability-induced OA models. We demonstrate that miR-146a aggravated pro-inflammatory cytokines induced suppressing the expression of cartilage matrix-associated genes. We further identified calcium/calmodulin-dependent protein kinase II delta (Camk2d) and protein phosphatase 3, regulatory subunit B, beta isoform (Ppp3r2, also known as calcineurin B, type II) were essential targets of miR-146a in regulating cartilage homeostasis. Moreover, we found that surgical-induced OA mice treated with a miR-146a inhibitor significantly alleviated the destruction of articular cartilage via targeting Camk2d and Ppp3r2. These results suggested that miR-146a has a crucial role in maintaining cartilage homeostasis. MiR-146a inhibition in chondrocytes can be a potential therapeutic strategy to ameliorate OA.
Insights
MicroRNA-146a (miR-146a) accelerates osteoarthritis (OA) by suppressing cartilage genes. Inhibiting miR-146a in mice reduced cartilage damage, suggesting a new therapeutic approach for OA.
Area of Science:
- Biochemistry
- Molecular Biology
- Orthopedics
Background:
- Osteoarthritis (OA) pathogenesis is poorly understood, hindering effective treatment development.
- The role of microRNAs (miRNAs), specifically miR-146a, in OA pathophysiology remains largely unexplored.
Purpose of the Study:
- To investigate the specific function of miR-146a in osteoarthritis pathophysiology.
- To explore miR-146a as a potential therapeutic target for OA.
Main Methods:
- Utilized mouse models of spontaneous and instability-induced osteoarthritis.
- Employed miR-146a knockout (KO) mice and wild-type (WT) mice for comparative analysis.
- Investigated the effects of miR-146a inhibition in a surgical-induced OA mouse model.
Main Results:
- miR-146a knockout mice exhibited alleviated articular cartilage degeneration compared to WT mice.
- miR-146a was found to suppress cartilage matrix-associated genes, thereby aggravating pro-inflammatory cytokines.
- Camk2d and Ppp3r2 were identified as essential targets of miR-146a in regulating cartilage homeostasis.
- Treatment with a miR-146a inhibitor significantly reduced cartilage destruction in surgical-induced OA mice.
Conclusions:
- miR-146a plays a critical role in maintaining cartilage homeostasis.
- Inhibiting miR-146a in chondrocytes presents a potential therapeutic strategy for ameliorating osteoarthritis.