Abstract
Intervertebral disk degeneration (IVDD) is a spinal disk condition caused by an inflammatory response induced by various proinflammatory cytokines, such as interleukin (IL)-1β and tumor necrosis factor (TNF)-α. cyclin-dependent kinase 9 (CDK9) is a transcriptional regulator and potential therapeutic target for many diseases, especially in regulating the activation of primary inflammatory response genes. Our study investigated a highly selective CDK9 inhibitor, atuveciclib, which protects nucleus pulposus (NP) cells from proinflammatory stimuli-induced catabolism. The effects of CDK9 inhibition were determined in human and rat NP cells treated with IL-1β in the presence or absence of atuveciclib or small interfering RNA target CDK9. Inhibition of CDK9 led to the attenuation of inflammatory response. In addition, rat intervertebral disk (IVD) explants were used to determine the role of CDK9 inhibition in extracellular matrix degradation. The rat IVDD model also proved that CDK9 inhibition attenuated IVDD, as validated using magnetic resonance imaging and immunohistochemistry. Taken together, CDK9 is a potential therapeutic target to prevent IVDD.
Highlights
Low back pain, which is one of the most common injuries and the leading cause of disability worldwide, has traditionally been thought to be an age-related degeneration of the disk tissue (Hoy et al, 2014; Foster et al, 2018)
Multiple abnormal stimuli can increase the levels of inflammatory cytokines, including interleukin (IL)-1β and tumor necrosis factor (TNF)-α, which are strongly correlated with extracellular matrix (ECM) and nucleus pulposus (NP) cell survival (Risbud and Shapiro, 2014)
In addition to its potent and highly selective positive transcription elongation factor b (P-TEFb)/cyclin-dependent kinase 9 (CDK9) inhibitor, we investigated whether atuveciclib could effectively attenuate the inflammatory response in Intervertebral disk degeneration (IVDD) through CDK9 inhibition
Summary
Low back pain, which is one of the most common injuries and the leading cause of disability worldwide, has traditionally been thought to be an age-related degeneration of the disk tissue (Hoy et al, 2014; Foster et al, 2018). Aggrecan is the most common proteoglycan, accounting for up to 50% of the NP dry weight (Walker and Anderson, 2004; Kepler et al, 2013) Both MMP-13 and aggrecan are regulated during an inflammatory response and responsible for the degradation of ECM (Luo et al, 2019). Multiple abnormal stimuli can increase the levels of inflammatory cytokines, including interleukin (IL)-1β and tumor necrosis factor (TNF)-α, which are strongly correlated with ECM and NP cell survival (Risbud and Shapiro, 2014). These proinflammatory cytokines upregulate the generation of MMPs, and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) inhibit the expression of collagen 2 and aggrecan (Cheng et al, 2018). A strategy that could effectively attenuate the inflammatory response in IVD may prevent or delay the onset of IVDD
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