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Updated: May 24, 2025
Software-Assisted Quantitative Measurement of Osteoarthritic Subchondral Bone Thickness
Published on: March 18, 2022
Isoquercetin alleviates osteoarthritis via regulating the NOX4/Nrf2 redox imbalance in senescent chondrocytes
Siqi Zhou1, Fei Liao2, Haiyan Wen3
1Department of Orthopedics, Renmin Hospital of Wuhan University, Wuhan 430060, China.
Abstract:
The redox imbalance induced by excessive reactive oxygen species (ROS) contributes to senescent phenotypes of chondrocytes in osteoarthritis (OA). However, there is limited evidence regarding the involvement of NADPH oxidase-4 (NOX4)/NFE2-related factor 2 (Nrf2) redox imbalance in OA. Isoquercetin (IQ), a quercetin derivative, exhibits promising antioxidative and anti-aging properties. Here, we found that IQ promoted redox homeostasis by inhibiting NOX4 and activating Nrf2-mediated antioxidant responses, thereby ameliorating OA. Specifically, IQ significantly suppressed the expression of senescence-associated secretory phenotypes (SASPs) in senescent chondrocytes. RNA sequencing analysis revealed that cellular senescence and oxidative stress were involved in the mechanism of IQ's effect on senescent chondrocytes. IQ effectively reversed redox imbalance, as evidenced by reduced levels of ROS and endogenous oxidants, and increased mitochondrial membrane potential and, elevated levels of endogenous antioxidants. Mechanistically, the elevated expression of NOX4 observed in patients with severe OA confirms its role in OA pathogenesis. Molecular docking and NOX4 knockdown experiments suggested that IQ may interact with NOX4 and inhibit its expression. This study identifies a potential therapeutic target and provides a promising candidate for OA treatment.
Insights
Isoquercetin (IQ) combats osteoarthritis (OA) by restoring redox balance, inhibiting NADPH oxidase-4 (NOX4), and activating Nrf2 antioxidant pathways. This reduces chondrocyte senescence and ameliorates OA progression.
Area of Science:
- Biochemistry
- Cell Biology
- Medical Science
Background:
- Redox imbalance from reactive oxygen species (ROS) drives chondrocyte senescence in osteoarthritis (OA).
- The role of NADPH oxidase-4 (NOX4)/NFE2-related factor 2 (Nrf2) redox imbalance in OA pathogenesis is not well understood.
- Isoquercetin (IQ), a quercetin derivative, possesses known antioxidant and anti-aging properties.
Purpose of the Study:
- To investigate the therapeutic potential of Isoquercetin (IQ) in ameliorating osteoarthritis (OA).
- To elucidate the mechanism by which IQ affects redox homeostasis and chondrocyte senescence in OA.
- To explore the role of NOX4/Nrf2 signaling in IQ's OA-protective effects.
Main Methods:
- RNA sequencing to analyze cellular senescence and oxidative stress pathways.
- Measurement of reactive oxygen species (ROS) levels, mitochondrial membrane potential, and antioxidant levels.
- Molecular docking and NOX4 knockdown experiments to determine IQ-NOX4 interaction.
- Assessment of senescence-associated secretory phenotypes (SASPs) in chondrocytes.
Main Results:
- IQ treatment restored redox homeostasis by reducing ROS and increasing endogenous antioxidants.
- IQ significantly suppressed SASP expression in senescent chondrocytes.
- IQ inhibited NOX4 expression and activated Nrf2-mediated antioxidant responses.
- Elevated NOX4 expression was observed in severe OA patients, correlating with disease severity.
Conclusions:
- IQ effectively ameliorates OA by promoting redox balance through NOX4 inhibition and Nrf2 activation.
- IQ demonstrates potential as a therapeutic agent for OA by targeting chondrocyte senescence and oxidative stress.
- The NOX4/Nrf2 pathway is a critical target for IQ's beneficial effects in OA treatment.
