Accelerated aging of intervertebral discs in a mouse model of progeria.
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.
Ferguson Laboratory for Orthopaedic Research, Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA. von@upmc.edu
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Hyoung-Yeon
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Andria
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Robinson
Gwendolyn
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Sowa
Douglas
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Bentley
Lauren
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Taylor
Rebecca
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Studer
Arvydas
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Johnny
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Huard
Sean
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Alber
Simon C
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Watkins
Joon
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Paulo
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Coehlo
Dong
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Wang
Mattia
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Loppini
Paul D
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Robbins
Laura J
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Niedernhofer
James
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Kang
D000375:Aging / Q000473:pathology*; D000818:Animals; D017209:Apoptosis; D016922:Cellular Senescence; D004268:DNA-Binding Proteins / Q000172:deficiency*; D004195:Disease Models, Animal; D004720:Endonucleases / Q000172:deficiency*; D007403:Intervertebral Disc / Q000473:pathology*; D055959:Intervertebral Disc Degeneration / Q000139:chemically induced / Q000473:pathology*; D008466:Mechlorethamine / Q000633:toxicity; D051379:Mice; D011371:Progeria / Q000473:pathology*; D011509:Proteoglycans / Q000378:metabolism
D004268:DNA-Binding Proteins; D011509:Proteoglycans; D008466:Mechlorethamine; D004720:Endonucleases; C499360:Ercc1 protein, mouse