Abstract
Approximately 40% of people under 30 and over 90% of people 55 or older suffer from moderate-to-severe levels of degenerative intervertebral disc (IVD) disease in their lumbar spines. Surgical treatments are sometimes effective; however, the treatment of back pain related to IVD degeneration is still a challenge; therefore, new treatments are necessary. Apoptosis may be important in IVD degeneration because suppressing cell apoptosis inside the IVD inhibits degeneration. Caspase-3, the primary effector of apoptosis, may be a key treatment target. We analyzed caspase-3’s role in two different types of IVD degeneration using caspase-3 knockout (Casp-3 KO) mice. Casp-3 KO delayed IVD degeneration in the injury-induced model but accelerated it in the age-induced model. Our results suggest that this is due to different pathological mechanisms of these two types of IVD degeneration. Apoptosis was suppressed in the IVD cells of Casp-3 KO mice, but cellular senescence was enhanced. This would explain why the Casp-3 KO was effective against injury-induced, but not age-related, IVD degeneration. Our results suggest that short-term caspase-3 inhibition could be used to treat injury-induced IVD degeneration.
Highlights
40% of people under 30 and over 90% of people 55 or older suffer from moderateto-severe levels of degenerative intervertebral disc (IVD) disease in their lumbar spines
Injury-induced IVD degeneration has been described in previous studies wherein increased gene expression of type I and II collagen, fibronectin, several metalloproteinases (MMP-1, -9, and -13), various growth factors, pro-inflammatory cytokines [tumor necrosis factor-alpha and interleukin-1 beta (IL-1β)]19,20, and the coexpression of FasL with Fas induce the apoptosis of disc cells[21]
We investigated whether the different pathological mechanisms in IRD and age-related IVD degeneration (ARD) affect the response to caspase-3 deletion and whether long-term caspase-3 inhibition results in tumorigenesis
Summary
40% of people under 30 and over 90% of people 55 or older suffer from moderateto-severe levels of degenerative intervertebral disc (IVD) disease in their lumbar spines. Apoptosis was suppressed in the IVD cells of Casp-3 KO mice, but cellular senescence was enhanced This would explain why the Casp-3 KO was effective against injury-induced, but not age-related, IVD degeneration. We previously studied disc cell apoptosis inhibition via a caspase-3 knockdown as a treatment target for IVD degeneration in rabbits[7,12]. Injury-induced IVD degeneration has been described in previous studies wherein increased gene expression of type I and II collagen, fibronectin, several metalloproteinases (MMP-1, -9, and -13), various growth factors (fibroblast growth factor and transforming growth factor-alpha), pro-inflammatory cytokines [tumor necrosis factor-alpha and interleukin-1 beta (IL-1β)]19,20, and the coexpression of FasL with Fas induce the apoptosis of disc cells[21]. An age-related spontaneous IVD degeneration model needs to be studied
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