Seventy to 85% of all people experience back pain at some time in life with direct costs of treatment being over $11.4 billion annually. Disorders of the intervertebral disc are commonly implicated in low back pain patients and are often associated with mechanical overloading. The outcome of the proposed work will be publications that develop a quantitative understanding of how healthy and damaging mechanical loading will influence intervertebral disc remodeling in vivo. We believe that understanding this remodeling response at the molecular level will provide a necessary foundation for development of a broad range of future treatment modalities including manual therapies as well as biological methods of tissue repair and replacement. The combined mechanical and biological aims are consistent with high priority funding topic areas defined at the 4th NIH/BECON Symposium 2001, Reparative Medicine: Growing Tissues and Organs. We first perform short-term 'screening'experiments to determine the effects of: 1) load duration and recovery time after load, and 2) torsional shear magnitude and frequency on the intervertebral disc cell anabolic and catabolic gene expression responses using a rat tail model. An external fixator will be surgically installed into the tail vertebrae of rats in vivo to allow precise mechanical control over the intervertebral joint loading conditions. Quantitative measurement of the relative mRNA expression of 8 important structural proteins and proteases will be made using real time RT-PCR. These initial screening tests will define those mechanical loading conditions that promote significant and specific alterations in mRNA expression that are anticipated to lead to changes in composition and structure. These short-term experiments are used to define a quantitative relationship between intervertebral joint loading and gene expression. The goal of Aim 3 is to perform a chronic study to evaluate how chronic mechanical loading leads to disc remodeling including the progression of disc degeneration. Intervertebral disc remodeling will be evaluated through measurement of composition, structure, and mechanical properties in addition to gene expression after 14 days and 56 days of continued loading. The chronic experiments will evaluate how changes in the message levels and enzyme activation/inhibition may lead to alterations in protein content and disc structure.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR051146-09
Application #
8386938
Study Section
Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
Tyree, Bernadette
Project Start
2005-03-01
Project End
2013-11-30
Budget Start
2012-12-01
Budget End
2013-11-30
Support Year
9
Fiscal Year
2013
Total Cost
$322,196
Indirect Cost
$132,110
Name
Icahn School of Medicine at Mount Sinai
Department
Orthopedics
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Martin, John T; Gullbrand, Sarah E; Fields, Aaron J et al. (2018) Publication trends in spine research from 2007 to 2016: Comparison of the Orthopaedic Research Society Spine Section and the International Society for the Study of the Lumbar Spine. JOR Spine 1:e1006
Illien-Jünger, Svenja; Lu, Young; Qureshi, Sheeraz A et al. (2015) Chronic ingestion of advanced glycation end products induces degenerative spinal changes and hypertrophy in aging pre-diabetic mice. PLoS One 10:e0116625
Cornejo, M C; Cho, S K; Giannarelli, C et al. (2015) Soluble factors from the notochordal-rich intervertebral disc inhibit endothelial cell invasion and vessel formation in the presence and absence of pro-inflammatory cytokines. Osteoarthritis Cartilage 23:487-96
(2014) Abstracts of the Anatomical Society Summer Meeting 2013, July 4-5, 2013, Dublin, Ireland. J Anat 224:228-49
Illien-Jünger, Svenja; Lu, Young; Purmessur, Devina et al. (2014) Detrimental effects of discectomy on intervertebral disc biology can be decelerated by growth factor treatment during surgery: a large animal organ culture model. Spine J 14:2724-32
Lu, Young; Guzman, Javier Z; Purmessur, Devina et al. (2014) Nonoperative management of discogenic back pain: a systematic review. Spine (Phila Pa 1976) 39:1314-24
Walter, B A; Illien-Jünger, S; Nasser, P R et al. (2014) Development and validation of a bioreactor system for dynamic loading and mechanical characterization of whole human intervertebral discs in organ culture. J Biomech 47:2095-101
Purmessur, D; Walter, B A; Roughley, P J et al. (2013) A role for TNF? in intervertebral disc degeneration: a non-recoverable catabolic shift. Biochem Biophys Res Commun 433:151-6
Purmessur, Devina; Guterl, Clare C; Cho, Samuel K et al. (2013) Dynamic pressurization induces transition of notochordal cells to a mature phenotype while retaining production of important patterning ligands from development. Arthritis Res Ther 15:R122
Illien-Junger, Svenja; Grosjean, Fabrizio; Laudier, Damien M et al. (2013) Combined anti-inflammatory and anti-AGE drug treatments have a protective effect on intervertebral discs in mice with diabetes. PLoS One 8:e64302

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