SIRT1 expression is refractory to hypoxia and inflammatory cytokines in nucleus pulposus cells: Novel regulation by HIF-1α and NF-κB signaling

Hypoxia and a marked increase in inflammatory cytokines are common hallmarks of intervertebral disc degeneration; these events disrupt the normal balance between extracellular matrix (ECM) degradation and synthesis in degenerative intervertebral discs. SIRT1, one of the NAD+-dependent class III histone deacetylases, controls cellular processes and is regulated by hypoxia and inflammatory cytokines in a cell-type-dependent manner. SIRT1 protects degenerative human nucleus pulposus cells against apoptosis. However, the role of SIRT1 in inflammation in intervertebral discs is still unclear. The current study showed that in rat NP cells, as in other cells, SIRT1 suppressed the induction of the mRNA expression of proteases that degrade ECM induced by TNF-alpha. Moreover, real-time PCR, transfection, and loss-and gain-of-function experiments revealed that SIRT1 mRNA and protein expression were refractory to hypoxia and HIF-1 alpha. Additionally, SIRT1 mRNA and protein expression and the activity of the SIRT1 promoter were not affected by inflammatory cytokines but were sustained by NF-kappa B signaling in the presence or absence of TNF-alpha. In summary, the present study suggested that SIRT1 is not affected by hypoxia and inflammatory cytokines in rat intervertebral discs. Moreover, not HIF-1 alpha but NF-kappa B signaling is critical for the maintenance of SIRT1 expression in NP cells under physiologic and pathophysiologic conditions.