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Updated: May 5, 2026
Software-Assisted Quantitative Measurement of Osteoarthritic Subchondral Bone Thickness
Published on: March 18, 2022
miR-708-5p Attenuates Osteoarthritis Progression via Multi-Target Modulation of the NOX4/NF-κB Axis and Cartilage
Shih-Hao Huang1, Zi Miao Liu1, Shu-Jung Chen1
1Department of Orthopaedic Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
Abstract:
ObjectiveTo investigate the novel role of miR-708-5p in osteoarthritis (OA) and its potential as a therapeutic target through regulation of NOX4/NF-κB signaling.MethodsExpression levels of miR-708-5p were analyzed in OA cartilage using GEO datasets and validated in interleukin (IL)-1β-treated primary human chondrocytes. Gain- and loss-of-function experiments were performed using miR-708-5p mimics and inhibitors to evaluate its effects on inflammation, extracellular matrix metabolism, apoptosis, and oxidative stress. Direct targeting of NOX4 by miR-708-5p was confirmed through bioinformatic prediction, luciferase reporter assays, and rescue experiments.ResultsmiR-708-5p was significantly downregulated in OA cartilage and IL-1β-treated chondrocytes. Overexpression of miR-708-5p attenuated IL-1β-induced inflammatory responses by suppressing pro-inflammatory cytokines (IL-1β, IL-6, tumor necrosis factor [TNF]-α), inhibiting matrix-degrading enzymes (MMP3, ADAMTS-4), and enhancing anabolic factors (COL2A1, SOX9). miR-708-5p protected against chondrocyte apoptosis by regulating Bcl2/BAX and caspase-3 expression. It also increased chondrocyte proliferation in EdU assays and reduced reactive oxygen species (ROS) production. Mechanistically, miR-708-5p directly inhibited NOX4, reducing ROS generation and nuclear factor kappa B (NF-κB) activation. NOX4 overexpression reversed the protective effects of miR-708-5p, confirming the functional significance of this regulatory axis.ConclusionmiR-708-5p is downregulated in OA and exerts chondroprotective effects. These findings suggest that restoring miR-708-5p expression may effectively suppress the NOX4/NF-κB axis and modulate chondrocyte inflammation, oxidative stress, apoptosis, and matrix degradation.
Insights
MicroRNA-708-5p is reduced in osteoarthritis (OA) and protects cartilage by inhibiting NOX4/NF-κB signaling. Restoring miR-708-5p may offer a new therapy for OA by reducing inflammation and cell death.
Area of Science:
- Biochemistry
- Molecular Biology
- Cell Biology
Background:
- Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage breakdown, inflammation, and oxidative stress.
- MicroRNAs (miRNAs) play crucial roles in regulating cellular processes relevant to OA pathogenesis.
- Identifying novel therapeutic targets is essential for managing OA progression.
Purpose of the Study:
- To investigate the role of miR-708-5p in osteoarthritis.
- To explore the potential of miR-708-5p as a therapeutic target.
- To elucidate the regulatory mechanism involving NOX4/NF-κB signaling.
Main Methods:
- Analysis of miR-708-5p expression in OA cartilage and human chondrocytes.
- Gain- and loss-of-function experiments to assess miR-708-5p effects on chondrocyte biology.
- Bioinformatic prediction, luciferase reporter assays, and rescue experiments to confirm direct targeting of NOX4.
- Evaluation of inflammatory markers, extracellular matrix components, apoptosis, and oxidative stress.
Main Results:
- miR-708-5p was significantly downregulated in OA cartilage and IL-1β-treated chondrocytes.
- Overexpression of miR-708-5p attenuated inflammation, matrix degradation, and apoptosis while enhancing anabolic factors and proliferation.
- miR-708-5p directly inhibited NOX4, reducing reactive oxygen species (ROS) and nuclear factor kappa B (NF-κB) activation.
- NOX4 overexpression reversed the protective effects of miR-708-5p.
Conclusions:
- miR-708-5p exhibits chondroprotective properties in osteoarthritis.
- Restoring miR-708-5p expression can suppress the NOX4/NF-κB axis.
- miR-708-5p represents a potential therapeutic strategy for modulating OA pathogenesis.
