ISSLS Prize Winner: Inhibition of NF-κB Activity Ameliorates Age-Associated Disc Degeneration in a Mouse Model of Accelerated Aging
NF-κB 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-κB-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-κB 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-κB 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-κB inhibition on IDD, using a DNA repair-deficient mouse model of accelerated aging (Ercc1−/Δ mice) previously been reported to exhibit age-related IDD.Methods.
Systemic inhibition of NF-κB activation was achieved either genetically by deletion of 1 allele of the NF-κB subunit p65 (Ercc1−/Δp65+− 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-κB, IκB Inducible Kinase (IKK), in Ercc1−/Δ 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-κB activity were observed in discs of progeroid Ercc1−/Δ mice and naturally aged wild-type mice compared with young wild-type mice. Systemic inhibition of NF-κB by the 8K-NBD peptide in Ercc1−/Δ 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−/Δp65+/− mice.Conclusion.
These findings demonstrate that the IKK/NF-κB signaling pathway is a key mediator of age-dependent IDD and represents a therapeutic target for mitigating disc degenerative diseases associated with aging.