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Accelerated aging of intervertebral discs in a mouse model of progeria

Vo, N and Seo, HY and Robinson, A and Sowa, G and Bentley, D and Taylor, L and Studer, R and Usas, A and Huard, J and Alber, S and Watkins, SC and Lee, J and Coehlo, P and Wang, D and Loppini, M and Robbins, PD and Niedernhofer, LJ and Kang, J (2010) Accelerated aging of intervertebral discs in a mouse model of progeria. Journal of Orthopaedic Research, 28 (12). 1600 - 1607. ISSN 0736-0266

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Abstract

Intervertebral disc degeneration (IDD) is a common and debilitating disorder that results in reduced flexibility of the spine, pain, and reduced mobility. Risk factors for IDD include age, genetic predisposition, injury, and other environmental factors such as smoking. Loss of proteoglycans (PGs) contributes to IDD with advancing age. Currently there is a lack of a model for rapid investigation of disc aging and evaluation of therapeutic interventions. Here we examined progression of disc aging in a murine model of a human progeroid syndrome caused by deficiency of the DNA repair endonuclease, ERCC1-XPF (Ercc1-/Δ mice). The ERCC1-deficient mice showed loss of disc height and degenerative structural changes in their vertebral bodies similar to those reported for old rodents. Compared to their wild-type littermates, Ercc1-/Δ mice also exhibit other age-related IDD characteristics, including premature loss of disc PG, reduced matrix PG synthesis, and enhanced apoptosis and cell senescence. Finally, the onset of age-associated disc pathologies was further accelerated in Ercc1 -/Δ mice following chronic treatment with the chemotherapeutic agent mechlorethamine. These results demonstrate that Ercc1-/Δ mice represent an accurate and rapid model of disc aging and provide novel evidence that DNA damage negatively impacts PG synthesis. © 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Vo, Nnvv1@pitt.eduNVV1
Seo, HY
Robinson, A
Sowa, Ggas26@pitt.eduGAS26
Bentley, D
Taylor, L
Studer, R
Usas, A
Huard, J
Alber, S
Watkins, SCsimon.watkins@pitt.eduSWATKINS
Lee, Jjol16@pitt.eduJOL16
Coehlo, P
Wang, D
Loppini, M
Robbins, PDprobb@pitt.eduPROBB
Niedernhofer, LJniedernh@pitt.eduNIEDERNH
Kang, Jjdkang@pitt.eduJDKANG
Centers: Other Centers, Institutes, or Units > Center for Biologic Imaging
Other Centers, Institutes, or Units > Hillman Cancer Center
Other Centers, Institutes, or Units > Stem Cell Research Center
Date: 1 December 2010
Date Type: Publication
Journal or Publication Title: Journal of Orthopaedic Research
Volume: 28
Number: 12
Page Range: 1600 - 1607
DOI or Unique Handle: 10.1002/jor.21153
Schools and Programs: Graduate School of Public Health > Human Genetics
School of Medicine > Cell Biology
School of Medicine > Microbiology and Molecular Genetics
School of Medicine > Orthopaedic Surgery
School of Medicine > Physical Medicine and Rehabilitation
Refereed: Yes
ISSN: 0736-0266
MeSH Headings: Aging--pathology; Animals; Apoptosis; Cell Aging; DNA-Binding Proteins--deficiency; Disease Models, Animal; Endonucleases--deficiency; Intervertebral Disc--pathology; Intervertebral Disc Degeneration--chemically induced; Intervertebral Disc Degeneration--pathology; Mechlorethamine--toxicity; Mice; Progeria--pathology; Proteoglycans--metabolism
Other ID: NLM NIHMS406888, NLM PMC3477798
PubMed Central ID: PMC3477798
PubMed ID: 20973062
Date Deposited: 04 Apr 2014 16:45
Last Modified: 02 Feb 2019 16:56
URI: http://d-scholarship.pitt.edu/id/eprint/20942

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