Accelerated aging of intervertebral discs in a mouse model of progeria

Nam Vo, Hyoung Yeon Seo, Andria Robinson, Gwendolyn Sowa, Douglas Bentley, Lauren Taylor, Rebecca Studer, Arvydas Usas, Johnny Huard, Sean Alber, Simon C. Watkins, Joon Lee, Paulo Coehlo, Dong Wang, Mattia Loppini, Paul D. Robbins, Laura J. Niedernhofer, James Kang

Research output: Contribution to journalArticlepeer-review

62 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1600-1607
Number of pages8
JournalJournal of Orthopaedic Research
Volume28
Issue number12
DOIs
StatePublished - Dec 2010

Keywords

  • DNA repair
  • aging
  • intervertebral disc degeneration
  • mouse models
  • proteoglycan

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