BRD4 inhibition regulates MAPK, NF‐κB signals, and autophagy to suppress MMP‐13 expression in diabetic intervertebral disc degeneration

Abstract

Diabetes mellitus may lead to intervertebral disc degeneration (IVDD). Matrix metalloproteinase‐13 (MMP‐13) is one of the major catabolic factors in extracellular matrix (ECM) metabolism of nucleus pulposus cells (NPCs) and contributes to diabetic IVDD. Bromodomain‐containing protein 4 (BRD4) is a member of the bromodomain and extraterminal protein family and is implicated in chronic inflammation. Here, we report that the expression of BRD4 and MMP‐13 was elevated in diabetic nucleus pulposus tissues as well as in advanced glycation end products (AGEs)‐treated NPCs; also, the regulatory effect of BRD4 on MMP‐13 was studied. We found that MMP‐13 was regulated by MAPK and NF‐κB signaling as well as autophagy in AGEs‐treated NPCs. Next, we explored the role of BRD4 in regulation of MAPK, NF‐κB signaling, and autophagy. The results showed that BRD4 is the upstream regulator of all of these 3 factors, and inhibition of BRD4 may suppress MAPK and NF‐κB signaling while activating autophagy in AGEs‐treated NPCs. Finally, we demonstrated that BRD4 inhibition may suppress MMP‐13 expression in diabetic NPCs in vitro as well as in vivo; meanwhile, it may preserve ECM in diabetic rats. Our study demonstrates that inhibition of BRD4 may suppress MAPK and NF‐κB signaling and activate autophagy to suppress MMP‐13 expression in diabetic IVDD, and diabetic IVDD may be compromised by BRD4 inhibitors.—Wang, J., Hu, J., Chen, X., Huang, C., Lin, J., Shao, Z., Gu, M., Wu, Y., Tian, N., Gao, W., Zhou, Y., Wang, X., Zhang, X. BRD4 inhibition regulates MAPK, NF‐κB signals, and autophagy to suppress MMP‐13 expression in diabetic intervertebral disc degeneration. FASEB J. 33, 11555–11566 (2019). http://www.fasebj.org

Inhibition of Brd4 by JQ1 Promotes Functional Recovery From Spinal Cord Injury by Activating Autophagy

“…In addition, some experiments of the current study were performed with PC12 cells, and although this neural cell line has been commonly used in vitro for investigation of neurological diseases, the use of primary neurons would be more informative. As previously mentioned, Brd4 inhibition is associated with the regulation of the inflammation response, and intraperitoneal injection of JQ1 may also exert this effect on glial cells and infiltrative inflammation-related cells to improve functional recovery after SCI ( Wang et al, 2019b ; Brasier and Zhou, 2020 ). Furthermore, in consideration of the complex of autophagy regulation, attributing this regulation to AMPK-mTOR may be one-sided.…”

“…Brd4 was first shown to control the cell cycle and cell identity determination, with this protein being regarded as an essential regulator for maintaining cancer progression and metastasis and a promising target for anticancer treatment ( Yang et al, 2008 ; Liu et al, 2014 ; Donati et al, 2018 ). In addition, the results from an increasing number of studies has shown that Brd4 is involved in the development of pulmonary fibrosis ( Tian et al, 2016 ), cardiac hypertrophy ( Spiltoir et al, 2013 ), osteoarthritis and intervertebral disk degeneration ( An et al, 2018 ; Wang et al, 2019b ). In the central nervous system, Brd4 is believed to be highly associated with cerebellar neurogenesis, as inhibition of Brd4 blocked learning and resulted in memory deficits ( Korb et al, 2015 ; Penas et al, 2019 ).…”

Epigenetic Modifiers as Potential Therapeutic Targets in Diabetic Kidney Disease

“…BRD4 also modulates the induction of a senescence-associated secretory phenotype in islet cells [146]. Moreover, BET proteins regulate pancreatic development [148], and diabetic intervertebral disc degeneration [149]. Related to diabetes-induced tissue injury, in streptozotocin-induced diabetic mice, JQ1 suppressed cardiac fibrosis and improved cardiac function by modulating Caveolin-1/TGF-β1 signaling in cardio fibroblasts and inhibiting cardiomyocyte apoptosis [150].…”

LncRNA MALAT1 exhibits positive effects on nucleus pulposus cell biology in vivo and in vitro by sponging miR-503

“…Prevailing evidence suggests that miR-503 exerts diverse biological functions, such as osteoblast proliferation and apoptosis, which are potentially amenable to therapeutic manipulation for clinical application [13]. Additionally, in several cell lines, MALAT1 could regulate downstream MAPK and activator protein-1 (AP1) signaling pathways, which play a critical role in intervertebral disc degeneration [14][15][16]. However, the impact of MALAT1 on the MAPK/AP1 pathway in NPC has not been determined.…”