Intervertebral disc degeneration (IDD) is closely associated with low back pain, but its underlying mechanism remains unclear. Cholesterol is an essential nutrient in mammalian cells. Alterations in cholesterol levels lead to impairments in cell physiology, such as cell proliferation and signal transduction. Previous clinical studies demonstrated that hypercholesterolemia could be a potential risk factor for IDD, but how cholesterol induces IDD remains unknown. The current study aimed to explore the regulatory role of cholesterol in IDD development and the potential underlying mechanisms. It was found that different forms of cholesterol levels were elevated in degenerative nucleus pulposus (NP) tissues in both humans and Sprague–Dawley rats. Rats fed a high cholesterol diet (HCD) exhibited degenerative features in the lumbar intervertebral disc compared with those fed a standard diet. Interestingly, this effect could be abolished by cholesterol-lowering drug atorvastatin. In NP cells treated with TNF-α and IL-1β, a significantly higher level of cholesterol was observed. These results suggested a pivotal role of cholesterol in the progression of IDD. We also observed accelerated pyroptosis in NP cells and extracellular matrix (ECM) degradation in the rat NP cells treated with exogenous cholesterol. We further demonstrated that endoplasmic reticulum stress was responsible for cholesterol-induced pyroptosis and ECM degradation. Moreover, RNA-seq analysis revealed that the mature form of SREBP1 (mSREBP1), an important regulator of lipid metabolism, is involved in regulating endoplasmic reticulum stress in knockdown experiments. In conclusion, this study demonstrated that cholesterol could induce pyroptosis in NP cells and ECM degradation by activating endoplasmic reticulum stress through stimulating mSREBP1 in IDD.

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An imbalance between matrix synthesis and degradation is the hallmark of intervertebral disc degeneration while inflammatory cytokines contribute to the imbalance. Bromodomain and extra‐terminal domain (BET) family is associated with the pathogenesis of inflammation, and inhibition of BRD4, a vital member of BET family, plays an anti‐inflammatory role in many diseases. However, it remains elusive whether BRD4 plays a similar role in nucleus pulposus (NP) cells and participates in the pathogenesis of intervertebral disc degeneration. The present study aims to observe whether BRD4 inhibition regulates matrix metabolism by controlling autophagy and NLRP3 inflammasome activity. Besides, the relationship was investigated among nuclear factor κB (NF‐κB) signaling, autophagy and NLRP3 inflammasome in NP cells. Here, real‐time polymerase chain reaction, western blot analysis and adenoviral GFP‐LC3 vector transduction in vitro were used, and it was revealed that BRD4 inhibition alleviated the matrix degradation and increased autophagy in the presence or absence of tumor necrosis factor α. Moreover, p65 knockdown or treatment with JQ1 and Bay11‐7082 demonstrated that BRD4 inhibition attenuated NLRP3 inflammasome activity through NF‐κB signaling, while autophagy inhibition by bafilomycin A1 promoted matrix degradation and NLRP3 inflammasome activity in NP cells. In addition, analysis of BRD4 messenger RNA expression in human NP tissues further verified the destructive function of BRD4. Simply, BRD4 inhibition alleviates matrix degradation by enhancing autophagy and suppressing NLRP3 inflammasome activity through NF‐κB signaling in NP cells.

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Background Intervertebral disc degeneration (IDD) and vertebral endplate Modic changes (MCs) are common lumbar degenerative phenotypes related to low back pain (LBP). Dyslipidemia has been linked to LBP but its associations with IDD and MCs have not been fully elucidated. The present study aimed to address the possible link between dyslipidemia, IDD and MCs in the Chinese population. Methods 1035 citizens were enrolled in the study. The levels of serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG) were collected. IDD was evaluated based on the Pfirrmann grading system and subjects with an average grade ≥ 3 were defined as having degeneration. MCs were classified into typical types 1, 2 and 3. Covariables, including age, sex, BMI and fasting plasma glucose, were included for the adjustment of the logistic analyses. Results The degeneration group included 446 subjects while the nondegeneration group included 589 subjects. The degeneration group had significant higher levels of TC and LDL-C (p < 0.001) whereas TG and HDL-C were not significantly different between the two groups. TC and LDL-C concentrations were significantly positively correlated with average IDD grades (p < 0.001). Multivariate logistic regression revealed that high TC (≥ 6.2 mmol/L, adjusted OR = 1.775, 95% CI = 1.209–2.606) and high LDL-C (≥ 4.1 mmol/L, adjusted OR = 1.818, 95% CI = 1.123–2.943) were independent risk factors for IDD. Type 1 MC presented in 84 (8.12%) subjects, type 2 MC presented in 244 (23.57%) subjects, type 3 MC presented in 27 (2.61%) subjects and no MC was observed in the remaining 680 (65.70%) subjects. The type 2 MC group demonstrated a higher level of TC, but the association between serum lipids and MCs could not be confirmed in further multivariate logistic regression. Conclusions High TC (≥ 6.2 mmol/L) and LDL-C (≥ 4.1 mmol/L) concentrations were independent risk factors for IDD for citizens in China. However, the association between dyslipidemia and MCs could not be determined. The effect of excess serum cholesterol may be critical for IDD and cholesterol lowering treatment may provide new opportunities in the management of lumbar disc degeneration.