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Circadian Rhythm Factor Rev-Erbα Recruits NCoR-HDAC3 and Ameliorates Intervertebral Disc Degeneration via NF-κB/NLRP3 Signaling
35 Pages Posted: 10 Oct 2023
More...Abstract
Background: Intervertebral disc (IVD) is a greatly rhythmic tissue with a circularly low-load recovery from experiencing daily loading cycles, and previous studies simply investigated brain and muscle ARNT-like 1(BMAL1) deficiency mice susceptible to IVD degeneration and low back pain. This study aimed to investigate the role, mechanism and potential therapeutic target of transcriptional repressor Rev-erbα for the IVD degeneration.
Methods: Expression of Rev-erbα was analyzed in human nuleeus pulposus (NP) tissues of mild and severe IVD degeneraion. Rev-erbα deficiency mice was performed to detect its fuction in aging or abnormal mechanical stress induced IVD degeneration. Rev-erbα knockdown in human primary NP cells induced by rhIL1β was used to investigate molecular mechanisms. Rev-erbα performed transcriptional repressin via its ligand heme was further identified by Co-inmunoprecipitation.
Findings: Our manuscript demonstrated lower Rev-erbα expression levels in aging or abnormal mechanical stress induced IVD degeneration. Rev-erbα deficiency accelerated IVD degeneration induced by aging or abnormal mechanical stress, which characterized with increased extracellular matrix catabolism and nucleus pulposus cell apoptosis. Mechanically, Rev-erbα knockdown in NP cells aggravates rhIL1β-induced NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation directly or via NF-κB signaling. Rev-erbα repressed NLRP3 inflammasome activation via its ligand heme bingding to nuclear receptor corepressor (NCoR) and histone deacetylase 3 (HDAC3). Pharmacological activation of Rev-erbα in vivo and vitro alleviated IVD degeneration via NF-κB/NLRP3 signaling. Targeting Rev-erbα may trigger off a valuable therapy for alleviating IVD degeneration and its related diseases.
Interpretation: Pharmacological activation of Rev-erbα alleviates IVD degeneration via its ligand heme bingding to nuclear receptor corepressor (NCoR) and histone deacetylase 3 (HDAC3) corepressor complex to repress NLRP3 inflammasome activation.
Funding: Yong Qiu has received funding from Jiangsu Provincial Medical Innovation Center of Orthopedic Surgery (Grant No. CXZX202214), and Qingshuang Zhou has received funding from Postgraduate Research & Practice Innovation Program of Jiangsu Province (Grant No. KYCX22_3709).
Declaration of Interest: None.
Ethical Approval: Ethics Committee of Nanjing Drum Tower Hospital, Medical School of Nanjing University (No.2020- 028-01) approved the project, and the enrolled patients signed informed consent before surgery. All animal care and experimental procedures were in compliance with guidelines approved by the Nanjing First Hospital, Nanjing Medical Univeristy (DWSY-22026152).
Keywords: Intervertebral disc, Intervertebral disc degeneration, Rev-erbα, Circadian rhythm, NLRP3, Heme
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