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The silencing of miR-199a-5p protects the articular cartilage through MAPK4 in osteoarthritis

Hanyu Lu¹, Yixin Yang¹, Shuanji Ou¹

¹Department of Orthopedics, Guangdong Second Provincial General Hospital, Guangzhou, China.

Annals of Translational Medicine

|June 20, 2022

Abstract

Background:

Osteoarthritis (OA) is the most common joint disorder, and places a heavy burden on individuals and society. As conventional therapies, such as surgery, rarely cure the disorder, targeted therapies represent a promising alternative. This research sought to explore the potential effect of miR-199a-5p on the development of OA.

Methods:

Based on the OA rat model, the serum was collected at 6 and 12 weeks, and microRNA (miRNA) sequencing was performed. A bioinformatics analysis was conducted to examine the differentially expressed micro ribonucleic acids, and qRT-PCR (real-time quantitative PCR) was conducted to determine their expression in the joint tissues of rats with OA. Rats articular chondrocytes were collected and treated with a miR-199a-5p antagomir or agomir. Afterwards, cell viability, autophagy was determinated. Dual luciferase was used to verify that miR-199a-5p targets the regulation of mitogen-stimulated protein kinase 4 (MAPK4). Subsequently, in chondrocytes, MAPK was knockdown to rescue the effect of miR-199a-5p inhibition, and cell viability and autophagy were examined. Finally, the OA model was treated with miR-199a-5p antagomir to detect joint pathology, cartilage tissue and inflammatory factor and autophagy was measured.

Results:

MiR-199a-5p was greatly upregulated in OA, and miRNA was found to be differentially expressed in OA tissues. MAPK4 was identified to be a target gene of miR-199-5p. Inhibiting miR-199a-5p not only decreased the survival of chondrocytes and induced apoptosis, but also relieved inflammation and decreased the content of pro-inflammatory cytokines. Further, the silencing of miR-199a-5p protected the articular cartilage and improved gait abnormalities, but this effect was abrogated by the silencing of MAPK4.

Conclusions:

The silencing of miR-199a-5p appears to improve gait abnormalities, promote the survival of chondrocytes, and improve the condition of OA. Our findings may lead to the development of miR-199a-5p-based targeted therapy for OA.

Insights

Silencing miR-199a-5p shows promise for osteoarthritis (OA) treatment by improving chondrocyte survival and reducing inflammation. This targeted therapy approach could offer new hope for managing this common joint disorder.

Area of Science:

Biomedical Research
Molecular Biology
Genetics

Background:

Osteoarthritis (OA) is a prevalent joint disorder causing significant individual and societal burden.
Conventional OA therapies often fall short, highlighting the need for effective targeted treatments.
MicroRNAs (miRNAs) are emerging as key regulators in OA pathogenesis.

Purpose of the Study:

To investigate the role of miR-199a-5p in the development of osteoarthritis.
To identify potential molecular targets regulated by miR-199a-5p in OA.
To explore the therapeutic potential of modulating miR-199a-5p in an OA model.

Main Methods:

Utilized an OA rat model, performing miRNA sequencing and bioinformatics analysis.
Employed qRT-PCR to validate miRNA expression in OA joint tissues.
Investigated the effects of miR-199a-5p modulation on chondrocyte viability, autophagy, and apoptosis in vitro.
Verified MAPK4 as a direct target of miR-199a-5p using dual-luciferase assays.
Assessed the impact of miR-199a-5p inhibition on joint pathology, cartilage, and inflammation in vivo.

Main Results:

miR-199a-5p was significantly upregulated in OA tissues.
MAPK4 was identified as a direct target gene of miR-199a-5p.
Inhibition of miR-199a-5p reduced chondrocyte apoptosis, relieved inflammation, and decreased pro-inflammatory cytokines.
Silencing miR-199a-5p protected articular cartilage and improved gait abnormalities in the OA model.
The protective effects of miR-199a-5p silencing were dependent on MAPK4 expression.

Conclusions:

miR-199a-5p plays a crucial role in OA development.
Targeting miR-199a-5p offers a promising therapeutic strategy for osteoarthritis.
Modulating miR-199a-5p can improve chondrocyte survival, reduce inflammation, and ameliorate OA symptoms.

Read full analysis

Keywords:

MAPK4 Osteoarthritis (OA)chondrocytes miR-199a-5p

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