The Caspase-3 Knockout Inhibits Intervertebral Disc Degeneration Related to Injury But Accelerates Degeneration Related to Aging

Abstract

Background: 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, including discectomy or fusion, are effective; however, several complications have been reported, so 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. Methods: To investigate whether the different pathological mechanisms in injury- (IRD) and age-related IVD degeneration (ARD) affect the response to caspase-3 deletion and whether long term inhibition of caspase-3 results in tumorigenesis, we analyzed the role of the caspase-3 in IRD and ARD models using caspase-3 knockout (Casp-3 KO) mice. Findings: 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. Specifically, we found that apoptosis is the primary driving factor in injury-related IVD degeneration, but cellular senescence, but not apoptosis, seems to be the primary driving factor in age-related IVD degeneration. Interpretation: The present results suggest that short-term caspase-3 inhibition could be used in the treatment of IRD and provide further evidence that anti-apoptotic treatment of IVD degeneration represents a new avenue of investigation for treating spinal trauma. Funding Statement: Grant-in-Aid for the Ministry of Education, Culture, Sports, Science, and Technology of Japan (26670651 and 17K16669). Declaration of Interests: The authors state: There are no competing interests. Ethics Approval Statement: All animal procedures in this study were approved by the Institutional Animal Care and Use Committee of Hokkaido University. All procedures were carried out in accordance with the approved guidelines.