Genotoxic stress accelerates age-associated degenerative changes in intervertebral discs

Luigi A. Nasto, Dong Wang, Andria R. Robinson, Cheryl L. Clauson, Kevin Ngo, Qing Dong, Peter Roughley, Michael Epperly, Saiful M. Huq, Enrico Pola, Gwendolyn Sowa, Paul D. Robbins, James Kang, Laura J. Niedernhofer, Nam V. Vo

Research output: Contribution to journalArticlepeer-review

36 Scopus citations


Intervertebral disc degeneration (IDD) is the leading cause of debilitating spinal disorders such as chronic lower back pain. Aging is the greatest risk factor for IDD. Previously, we demonstrated IDD in a murine model of a progeroid syndrome caused by reduced expression of a key DNA repair enzyme. This led us to hypothesize that DNA damage promotes IDD. To test our hypothesis, we chronically exposed adult wild-type (Wt) and DNA repair-deficient Ercc1-/Δ mice to the cancer therapeutic agent mechlorethamine (MEC) or ionization radiation (IR) to induce DNA damage and measured the impact on disc structure. Proteoglycan, a major structural matrix constituent of the disc, was reduced 3-5× in the discs of MEC- and IR-exposed animals compared to untreated controls. Expression of the protease ADAMTS4 and aggrecan proteolytic fragments was significantly increased. Additionally, new PG synthesis was reduced 2-3× in MEC- and IR-treated discs compared to untreated controls. Both cellular senescence and apoptosis were increased in discs of treated animals. The effects were more severe in the DNA repair-deficient Ercc1-/Δ mice than in Wt littermates. Local irradiation of the vertebra in Wt mice elicited a similar reduction in PG. These data demonstrate that genotoxic stress drives degenerative changes associated with IDD.

Original languageEnglish (US)
Pages (from-to)35-42
Number of pages8
JournalMechanisms of Ageing and Development
Issue number1-2
StatePublished - Jan 2013

Bibliographical note

Funding Information:
We thank Dr. Yong Yang for his technical assistance on the local irradiation of the mouse tail and spine. This work was supported by NIH grant AG033046 and the 2010 ORS Collaborative Exchange Award (Nam Vo), NIH ES016114 and the University of Pittsburgh Claude D. Pepper Center ( P30AG024827 ) (Laura Niedernhofer), NIH AR051456 (Paul Robbins), and the Albert B. Ferguson, Jr. M.D. Orthopaedic Fund of the Pittsburgh Foundation . This project used the UPCI Animal Facility and was supported in part by award P30CA047904.


  • Aging
  • DNA damage
  • Genotoxic stress
  • Intervertebral disc
  • Matrix proteoglycan


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