|The Regeneration Lab Discuss 2012 ISSLS Prize Winner: Age Associated Disc Degeneration, Nf-kB inhibit: Spine 2012 in the General Discussion forums; NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) is a protein complex that controls the transcription of DNA Wikipedia.link Spine ...|
2012 ISSLS Prize Winner: Age Associated Disc Degeneration, Nf-kB inhibit: Spine 2012
NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) is a protein complex that controls the transcription of DNA Wikipedia.link
Spine (Phila Pa 1976). 2012 Feb 16. [Epub ahead of print]
(C) 2012 Lippincott Williams & Wilkins, Inc.
Issls Prize Winner: Inhibition of Nf-kb Activity Ameliorates Age-associated Disc Degeneration in a Mouse Model of Accelerated Aging.
Nasto LA, Seo HY, Robinson AR, Tilstra JS, Clauson CL, Sowa GA, Ngo K, Dong Q, Pola E, Lee JY, Niedernhofer LJ, Kang JD, Robbins PD, Vo NV.
1 Ferguson Laboratory for Orthopaedic Research, Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh PA 15261.
2 Department of Orthopaedic Surgery, Catholic University of Rome School of Medicine, "A. Gemelli" University Hospital, l.go Agostino Gemelli 8, 00168 Roma, Italy
3 Department of Orthopaedics, Chonnam National University Medical School Hak 1 dong 8, Gwangju, S Korea 501-757.
4 University of Pittsburgh Cancer Institute, Hillman Cancer Center, Pittsburgh PA 15213.
5 Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh PA 15219
6 Department of Physical Medicine and Rehabilitation, University of Pittsburgh School of Medicine, Pittsburgh PA 15261.
NF-[kappa]B activity was pharmacologically and genetically blocked in an accelerated aging mouse model to mitigate age-related disc degenerative changes.
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 which 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.
Systemic inhibition of NF-[kappa]B activation was achieved either genetically by deletion of one allele of the NF-[kappa]B subunit p65 (Ercc1-/[DELTA]p65+/- mice) or pharmacologically by chronic intra-peritoneal 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.
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 compared to young WT mice. Systemic inhibition of NF-[kappa]B by the 8K-NBD peptide in Ercc1-/[DELTA] mice increased disc proteoglycan synthesis and ameriolated loss disc cellularity and matrix proteoglycan. These results were confirmed genetically by using the p65 haploinsufficient Ercc1-/[DELTA]p65+/- mice.
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.
|age-related degerneration, intervertebral disc|
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