Targeting clock-controlled gene Nrf2 ameliorates inflammation-induced intervertebral disc degeneration

Area of Science:

• Biomedical Science
• Chronobiology
• Musculoskeletal Research

Background:

• Intervertebral disc (IVD) homeostasis relies on a diurnal mechanical loading cycle.
• Disruption of the IVD circadian clock is linked to intervertebral disc degeneration (IDD).
• The role of inflammation in disturbing the IVD clock and inducing IDD remains unclear.

Purpose of the Study:

• To investigate if inflammation disrupts the IVD clock and induces IDD.
• To explore the mechanism by which a dampened IVD clock leads to IDD.
• To identify potential therapeutic targets for IDD.

Main Methods:

• Induced IDD using IL-1β in nucleus pulposus (NP) tissues and cells.
• Knocked down the core clock gene Bmal1 to disrupt the NP cell circadian clock.
• Assessed the expression of NRF2 and inflammatory markers.
• Utilized an organotypic tissue-explant model to evaluate NRF2 activation.

Main Results:

• Inflammation (IL-1β) dampened the IVD clock in human and rat NP tissues and cells.
• Bmal1 knockdown disrupted the NP cell circadian clock, causing cell dysfunction.
• Bmal1 knockdown reduced NRF2 expression, increasing inflammation, oxidative stress, and apoptosis.
• NRF2 activation mitigated NP cell dysfunction and tissue degeneration.

Conclusions:

• Inflammation disrupts the IVD clock, contributing to IDD.
• The Bmal1-NRF2 pathway is crucial in regulating NP cell function and IDD.
• Targeting NRF2 offers a potential therapeutic strategy for preventing and recovering from IDD.