title: Genotoxic stress accelerates age-associated degenerative changes in intervertebral discs.
abstract: 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.
authors.affiliation: Ferguson Laboratory for Orthopaedic Research, Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
authors.forename: Luigi A
authors.initials: LA
authors.lastname: Nasto
authors.forename: Dong
authors.initials: D
authors.lastname: Wang
authors.forename: Andria R
authors.initials: AR
authors.lastname: Robinson
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Clauson
authors.forename: Kevin
authors.initials: K
authors.lastname: Ngo
authors.forename: Qing
authors.initials: Q
authors.lastname: Dong
authors.forename: Peter
authors.initials: P
authors.lastname: Roughley
authors.forename: Michael
authors.initials: M
authors.lastname: Epperly
authors.forename: Saiful M
authors.initials: SM
authors.lastname: Huq
authors.forename: Enrico
authors.initials: E
authors.lastname: Pola
authors.forename: Gwendolyn
authors.initials: G
authors.lastname: Sowa
authors.forename: Paul D
authors.initials: PD
authors.lastname: Robbins
authors.forename: James
authors.initials: J
authors.lastname: Kang
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Niedernhofer
authors.forename: Nam V
authors.initials: NV
authors.lastname: Vo
mesh_terms: D051722:ADAM Proteins / Q000096:biosynthesis / Q000235:genetics; D000071121:ADAMTS4 Protein; D053674:Aggrecans / Q000235:genetics / Q000378:metabolism; D000375:Aging / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000477:Alkylating Agents / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D016922:Cellular Senescence / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D004720:Endonucleases / Q000096:biosynthesis / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D007403:Intervertebral Disc / Q000378:metabolism* / Q000473:pathology; D055959:Intervertebral Disc Degeneration / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008466:Mechlorethamine / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D011348:Procollagen N-Endopeptidase / Q000096:biosynthesis / Q000235:genetics; D011839:Radiation, Ionizing
chemical_list: D053674:Aggrecans; D000477:Alkylating Agents; D004268:DNA-Binding Proteins; D008466:Mechlorethamine; C071447:ERCC1 protein, human; D004720:Endonucleases; D051722:ADAM Proteins; D011348:Procollagen N-Endopeptidase; D000071121:ADAMTS4 Protein; C000603918:ADAMTS4 protein, human; C000603919:Adamts4 protein, mouse