The effect of advanced glycation end products (AGE's) on the biomechanical properties of cortical bone will be studied in murine models. It is known that AGE's form cross-links that compromise bone biomechanical properties. AGE's accumlate with age and are also found in certain disorders, including type 1 and type 2- diabetes. The project will employ a unique combination of tools: biomechanical measurements, Raman spectroscopy and solid state magic angle spinning nuclear magnetic resonance spectroscopy (MAS NMR) that will provide detailed information on material property changes in the crystal structure of bone mineral crystallites and in the collagen secondary structure as the bone is mechanically loaded. A custom-designed rotor that includes provision for applying compressive load will be used for elastic deformation MAS NMR experiments. External loading will be used to study chemical structure correlates of material properties beyond the yield point. We hypothesize that changes in the mineral will include mineral compression and distortion of the matrix collagen chain as cross-links are distorted and that these changes can be followed as changes in both NMR and Raman spectra of the bone. Ribose incubation will be used to generate AGE non-enzymatic cross-links in murine cortical bone. Variations in incubation time will be used to vary the cross-link abundance and will provide background information for further studies. With this background information, a study of age- dependence will be undertaken. We hypothesize that mineral compression and collagen distortion will increase with age. Next, we will study the AGE effects in NOD cortical bone, a mouse model for type 1 diabetes. We expect to see changes similar to those in the aging study, but that they will begin at earlier ages. We will also develop correlations between AGE levels and whole bone properties and between ultrastructural level composition data generated by NMR and whole bone properties, providing important insights into how ultrastructural changes translate into whole bone function and serve as predictors of skeletal fragility. Finally, we will develop correlations between the detailed structural information provided by MAS NMR and the less detailed information provided by Raman spectroscopy. These correlations will be used to increase the information gained from other Raman spectroscopic studies, especially non-invasive diagnostics for bone disorders.

Public Health Relevance

Advanced glycation end products accumulate with age and with progression of many disorders including type 1 and type 2-diabetes. AGE's lead to weaker bones and greater fracture risk, so it is important to understand exactly how AGE's operate in order to develop treatments that minimize the damage and diagnostic methods for early detection of their presence. Our project will provide this information.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR052010-06
Application #
8322050
Study Section
Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
Lester, Gayle E
Project Start
2005-01-07
Project End
2016-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
6
Fiscal Year
2012
Total Cost
$496,719
Indirect Cost
$173,873
Name
University of Michigan Ann Arbor
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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