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Published on: June 2, 2023
MicroRNA-218-5p as a Potential Target for the Treatment of Human Osteoarthritis
Jun Lu1, Ming-Liang Ji1, Xue-Jun Zhang1
1Department of Orthopaedic Surgery, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China.
Abstract:
Emerging evidence suggests that dysregulated microRNAs (miRNAs) play a pivotal role in osteoarthritis (OA), but the role of specific miRNAs remains unclear. Accordingly, we identified OA-associated miRNAs and functional validation of results. Here, we demonstrate that miR-218-5p is significantly upregulated in moderate and severe OA and correlates with scores on a modified Mankin scale. Through gain-of-function and loss-of-function studies, miR-218-5p was shown to significantly affect matrix synthesis gene expression and chondrocyte proliferation and apoptosis. Using SW1353 and C28/I2 cells, PIK3C2A mRNA was identified as a target of miR-218-5p. Downregulation of miR-218-5p dramatically promoted expression of PIK3C2A and its downstream target proteins, such as Akt, mTOR, S6, and 4EBP1. More importantly, OA mice exposed to a miR-218-5p inhibitor were protected from cartilage degradation and had reduced proteoglycan loss and reduced loss of articular chondrocyte cellularity compared with control mice. miR-218-5p is a novel inducer of cartilage destruction via modulation of PI3K/Akt/mTOR signaling. Inhibition of endogenous miR-218-5p expression/activity appears to be an attractive approach to OA treatment.
Insights
MicroRNA-218-5p (miR-218-5p) is elevated in osteoarthritis and drives cartilage destruction by impacting PI3K/Akt/mTOR signaling. Inhibiting miR-218-5p shows promise for treating osteoarthritis.
Area of Science:
- Biochemistry
- Molecular Biology
- Orthopedics
Background:
- Dysregulated microRNAs (miRNAs) are implicated in osteoarthritis (OA) pathogenesis.
- The specific roles of individual miRNAs in OA progression require further elucidation.
Purpose of the Study:
- To identify and functionally validate specific miRNAs associated with OA.
- To investigate the role of miR-218-5p in OA development and explore its therapeutic potential.
Main Methods:
- miRNA expression profiling in OA tissues.
- Gain-of-function and loss-of-function studies in chondrocyte cell lines (SW1353, C28/I2).
- In vivo studies using an OA mouse model with miR-218-5p inhibition.
Main Results:
- miR-218-5p is significantly upregulated in moderate to severe OA and correlates with Mankin scores.
- miR-218-5p modulates chondrocyte proliferation, apoptosis, and matrix synthesis gene expression.
- PIK3C2A was identified as a direct target of miR-218-5p, impacting the PI3K/Akt/mTOR pathway.
- Inhibition of miR-218-5p in OA mice protected against cartilage degradation and proteoglycan loss.
Conclusions:
- miR-218-5p is a novel inducer of cartilage destruction in OA through PI3K/Akt/mTOR signaling.
- Inhibiting miR-218-5p represents a potential therapeutic strategy for osteoarthritis treatment.
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