The Nrf2 Pathway Alleviates Overloading Force-Induced TMJ Degeneration by Downregulating Oxidative Stress Reactions

Abstract

Objective

Oxidative stress is involved in the mechanisms associated with temporomandibular joint (TMJ) diseases. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a crucial oxidative stress marker, but the specific mechanisms of its regulation in the early stages of mandibular condylar cartilage (MCC) degeneration remain unclear. This study aimed to explore the regulatory role of Nrf2 and its related oxidative stress signaling pathway in the early stage of MCC degeneration.

Materials and Methods

Overloading force-induced MCC degeneration was performed in wild-type and Nrf2 knockout mice, as well as in mice after treatment with the Nrf2 activator cardamonin. Changes in MCC degeneration and the expression of oxidative stress markers in the corresponding situations were observed.

Results

Nrf2 and NADPH oxidase 2 (NOX2) expression were elevated during early MCC degeneration induced by an overloading force. MCC degeneration was aggravated when Nrf2 was knocked out, accompanied by increased NOX2 and superoxide dismutase 2 (SOD2) expression. The MCC degeneration process was alleviated after cardamonin treatment, with activation of the Nrf2 pathway and decreased NOX2 and SOD2 expression.

Conclusion

Early MCC degeneration is accompanied by mild oxidative stress progression. Activated Nrf2 and related pathways could alleviate the degeneration of MCC.

Keywords:

• NF-E2-related factor 2
• oxidative stress
• temporomandibular joint
• cartilage
• mechanical force

Abbreviations

TMJ, temporomandibular joint; Nrf2, erythroid 2-related factor 2; MCC, mandibular condylar cartilage; NOX2, NADPH oxidase 2; SOD2, superoxide dismutase 2; ROS, reactive oxygen species; ESR, electron spin resonance; DCFHDA, 2’,7’-dichlorofluorescein-diacetate; PCR, polymerase chain reaction; SEM, scanning electron microscopy; DAPI, 4,6-diamidino-2-phenylindole; MMP13, matrix metalloproteinase 13; HO-1, heme oxygenase 1; NQO-1, NAD(P)H quinone dehydrogenase 1; Keap1, Kelch like ECH associated protein 1.

Ethical Statement

This study was approved by the Animal Ethics Committee of Chongqing Medical University (AECCMU-2020-004), and all experiments followed the National Institutes of Health’s Guidelines for the Care and Use of Laboratory Animals.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

All authors declare no conflicts of interest in this work.

Additional information

Funding

This work was supported by China Postdoctoral Science Foundation (2018M640902 to Y.H.).