ISSLS Prize Winner: Inhibition of NF-κB Activity Ameliorates Age-Associated Disc Degeneration in a Mouse Model of Accelerated Aging

Study Design. NF-kappa B activity was pharmacologically and genetically blocked in an accelerated aging mouse model to mitigate age-related disc degenerative changes. Objective. To study the mediatory role of NF-kappa B-signaling pathway in age-dependent intervertebral disc degeneration. Summary of Background Data. Aging is a major contributor to intervertebral disc degeneration (IDD), but the molecular mechanism behind this process is poorly understood. NF-kappa B is a family of transcription factors that play a central role in mediating cellular response to damage, stress, and inflammation. Growing evidence implicates chronic NF-kappa B activation as a culprit in many aging-related diseases, but its role in aging-related IDD has not been adequately explored. We studied the effects of NF-kappa B inhibition on IDD, using a DNA repair-deficient mouse model of accelerated aging (Ercc1(-/Delta) mice) previously been reported to exhibit age-related IDD. Methods. Systemic inhibition of NF-kappa B activation was achieved either genetically by deletion of 1 allele of the NF-kappa B subunit p65 (Ercc1(-/Delta)p65(+-) mice) or pharmacologically by chronic intraperitoneal administration of the Nemo Binding Domain (8K-NBD) peptide to block the formation of the upstream activator of NF-kappa B, I kappa B Inducible Kinase (IKK), in Ercc1(-/Delta) mice. Disc cellularity, total proteoglycan content and proteoglycan synthesis of treated mice, and untreated controls were assessed. Results. Decreased disc matrix proteoglycan content, a hallmark feature of IDD, and elevated disc NF-kappa B activity were observed in discs of progeroid Ercc1(-/Delta) mice and naturally aged wild-type mice compared with young wild-type mice. Systemic inhibition of NF-kappa B by the 8K-NBD peptide in Ercc1(-/Delta) mice increased disc proteoglycan synthesis and ameriolated loss of disc cellularity and matrix proteoglycan. These results were confirmed genetically by using the p65 haploinsufficient Ercc1(-/Delta)p65(+/-) mice. Conclusion. These findings demonstrate that the IKK/NF-kappa B signaling pathway is a key mediator of age-dependent IDD and represents a therapeutic target for mitigating disc degenerative diseases associated with aging.