Intervertebral disc degeneration (IDD) contributes to many spinal disorders such as chronic disabling low back pain, disc herniation, spinal stenosis and vertebral instability. IDD-associated back pain is the leading source of disability in people 45 years of age or younger, resulting in national economic losses estimated at more than 90 billion dollars a year in the United State alone. IDD is correlated with many diverse pathophysiologic etiologies, including genetics, smoking, mechanical injury, aging and other environmental factors, with aging being an inevitable and key contributor of IDD. Oxidative stress and genotoxic stress are widely accepted to contribute to aging in general10. However, whether oxidative or genotoxic stress are also a key culprits in disc aging has not been adequately explored due to a lack of a good animal model of age-related IDD. We recently demonstrated that a mouse model of accelerated aging (Ercc1-/ mice) caused by reduced expression of the DNA repair endonuclease ERCC1-XPF displays considerable disc matrix proteoglycan (PG) loss, a universal hallmark of disc aging, by five months of age. This leads us to hypothesize that accumulation of endogenous DNA damage plays a causal role in disc aging and PG loss. To test this hypothesis, two aims are proposed: (1) to determine if IDD is due to oxidative/genotoxic stress-induced disc cell senescence and death and loss of cell function, and (2) to determine if oxidative/genotoxic stress induces disc matrix PG degradation. The successful completion of these experiments will determine if there is a causal relationship between oxidative DNA damage and age- associated IDD and yield novel insights into the molecular causes of disc PG loss that will be useful for development of rational therapeutic interventions to prevent or delay IDD.

Public Health Relevance

These studies aim at understanding how aging intervertebral discs lose important matrix structural constituents in order to develop rational and effective treatment of spinal disorders such as chronic disabling low back pain.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AG033046-02
Application #
8128658
Study Section
Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
Williams, John
Project Start
2010-08-15
Project End
2013-07-31
Budget Start
2011-08-01
Budget End
2013-07-31
Support Year
2
Fiscal Year
2011
Total Cost
$149,262
Indirect Cost
Name
University of Pittsburgh
Department
Orthopedics
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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Nasto, Luigi A; Ngo, Kevin; Leme, Adriana S et al. (2014) Investigating the role of DNA damage in tobacco smoking-induced spine degeneration. Spine J 14:416-23
Nasto, Luigi A; Wang, Dong; Robinson, Andria R et al. (2013) Genotoxic stress accelerates age-associated degenerative changes in intervertebral discs. Mech Ageing Dev 134:35-42
Vo, Nam; Niedernhofer, Laura J; Nasto, Luigi Aurelio et al. (2013) An overview of underlying causes and animal models for the study of age-related degenerative disorders of the spine and synovial joints. J Orthop Res 31:831-7
Kim, Hye-Yeong; Mcclincy, Michael; Vo, Nam V et al. (2013) Functional probe for annulus fibrosus-targeted intervertebral disc degeneration imaging. J Biomed Opt 18:101308
Nasto, Luigi A; Robinson, Andria R; Ngo, Kevin et al. (2013) Mitochondrial-derived reactive oxygen species (ROS) play a causal role in aging-related intervertebral disc degeneration. J Orthop Res 31:1150-7
Vo, Nam V; Hartman, Robert A; Yurube, Takashi et al. (2013) Expression and regulation of metalloproteinases and their inhibitors in intervertebral disc aging and degeneration. Spine J 13:331-41
Wuertz, Karin; Vo, Nam; Kletsas, Dimitris et al. (2012) Inflammatory and catabolic signalling in intervertebral discs: the roles of NF-*B and MAP kinases. Eur Cell Mater 23:103-19; discussion 119-20
Nasto, Luigi A; Seo, Hyoung-Yeon; Robinson, Andria R et al. (2012) ISSLS prize winner: inhibition of NF-?B activity ameliorates age-associated disc degeneration in a mouse model of accelerated aging. Spine (Phila Pa 1976) 37:1819-25
Wang, D; Nasto, L A; Roughley, P et al. (2012) Spine degeneration in a murine model of chronic human tobacco smokers. Osteoarthritis Cartilage 20:896-905

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