Abstract
Intervertebral disc degeneration (IDD) is the most common chronic skeletal muscle degeneration disease. Although the underlying mechanisms remain unclear, nucleus pulposus (NP) autophagy, senescence, and apoptosis are known to play a critical role in this process. Previous studies suggest that bromodomain-containing protein 4 (BRD4) promotes senescent and apoptotic effects in several age-related degenerative diseases. It is not known, however, if BRD4 inhibition is protective in IDD. In this study, we explored whether BRD4 influenced IDD. In human clinical specimens, the BRD4 level was markedly increased with the increasing Pfirrmann grade. At the cellular level, BRD4 inhibition prevented IL-1β-induced senescence and apoptosis of NP cells and activated autophagy via the AMPK/mTOR/ULK1 signaling pathway. Inhibition of autophagy by 3-methyladenine (3-MA) partially reversed the antisenescence and antiapoptotic effects of BRD4. In vivo, BRD4 inhibition attenuated IDD. Taken together, the results of this study showed that BRD4 inhibition reduced NP cell senescence and apoptosis by induced autophagy, which ultimately alleviated IDD. Therefore, BRD4 may serve as a novel potential therapeutic target for the treatment of IDD.
Highlights
Low back pain is a common symptom of intervertebral disc (IVD) degeneration (IDD) and the most common cause of loss of work ability and reduced quality of life, imposing a considerable economic burden on the family and society [1–3]
To evaluate its relationship with Intervertebral disc degeneration (IDD) progression, we evaluated bromodomain-containing protein 4 (BRD4) expression in nucleus pulposus (NP) tissues of different degrees of degeneration
We evaluated whether inhibition of BRD4 suppresses IL-1β-induced apoptosis of human NP cells
Summary
Low back pain is a common symptom of intervertebral disc (IVD) degeneration (IDD) and the most common cause of loss of work ability and reduced quality of life, imposing a considerable economic burden on the family and society [1–3]. In the pathogenesis of IDD, the water content of nucleus pulposus (NP) tissue gradually decreases, large amounts of proteoglycan and collagen II are lost, and disrupted extracellular matrix (ECM) metabolism leads to loss of the function and structure of the IVD [8]. Inhibiting the senescence and apoptosis of NP cells has a protective effect on IDD [10, 13]. Autophagy is related to degenerative diseases (e.g., osteoarthritis, neurodegenerative diseases, and cancer) [14, 15], and is a protective mechanism activated by NP cells to suppress senescence and apoptosis. Studying the crosstalk of autophagy, senescence, and apoptosis in NP cells will provide insight into the pathogenesis of, and facilitate identification of potential therapeutic targets for, IDD. BRD4 inhibition delays IDD by regulating the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR)/Unc51-like autophagy-activating kinase (ULK1) signaling pathway to activate autophagy and inhibit the senescence and apoptosis of NP cells. BRD4 has therapeutic potential for preventing the progression of IDD
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