Introduction Chronic and debilitating low back pain is a common condition and a huge economic burden. Many cases are attributed to age-related degeneration of the intervertebral disc (IVD); however, age-related degeneration appears to occur at an accelerated rate in some individuals. We have previously demonstrated biomarkers of cellular senescence within the human IVD and suggested a role for senescence in IVD degeneration. Senescence occurs with ageing but can also occur prematurely in response to stress. We hypothesised that stress-induced premature senescence (SIPS) occurs within the IVD and here we have investigated the expression and production of caveolin-1, a protein that has been shown previously to be upregulated in SIPS.

RationaleRheumatoid arthritis (RA) is associated with accelerated atherosclerosis and premature cardiovascular death. Chronic inflammation mediated by tumour necrosis factor (TNF) may contribute to this by promoting endothelial activation, dysfunction and leukocyte recruitment. Anti-TNF therapy has been associated with improved vascular function in RA patients. However, the specific effects of TNF inhibitors on endothelial cell function are largely unknown. We aim to establish whether the anti-TNF therapy certolizumab pegol (CZP) (Cimzia®; UCB, Belgium) modulates the inflammatory response by activated human endothelial cells.Methods and ResultsHuman aortic endothelial cells (HAoECs) were cultured in vitro and exposed to (i) TNF alone, (ii) TNF plus CZP, or (iii) neither agent. Microarray analysis detected at least twofold higher expression of 115 genes after exposure of HAoEC to TNF, compared to control untreated cells. 22.6% of the increased genes were associated with the immune response and 9.6% encoded adhesion/cell surface molecules. In particular, genes for E-selectin, VCAM-1 and ICAM-1 were significantly upregulated by TNF treatment, which was validated by qPCR. Notably, treatment of HAoEC with the TNF/CZP cocktail prevented the up-regulation of these genes, resulting in an expression pattern similar to that detected in control cells. Immunocytochemistry confirmed the NFkB pathway as a downstream target of TNF-induced HAoEC activation, since the TNF-induced nuclear translocation of NFkB was prevented in the presence of CZP.ConclusionsThe clinically available anti-inflammatory agent CZP eliminates upregulation of adhesion molecules by endothelial cells. Whether this TNF inhibitor contributes to improved endothelial function in patients is currently under investigation.

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