Our objective is to determine the role that collagen cross-linking (both enzymatic- and non- enzymatically-mediated), collagen maturity (alpha/beta CTX), and the accumulation of advanced glycation end-products (AGE's) play in bone's structural and material energy absorption capacity.
Aim 1 will determine whether there is a significant accumulation of AGE's in bone following 2 or 3 years treatment with doses of bisphosphonate currently used to treat postmenopausal osteoporosis, or those used to treat Paget's disease. AGE accumulation will be correlated to toughness and normalized energy to failure.
This Aim uses dogs that have already been treated and sacrificed, but proposes material property measurements as well as analysis of collagen cross-linking and maturation that were not proposed in our original application.
Aim 2 will determine whether diabetic rats, known to accumulate AGE's in bone, show changes in toughness and normalized energy to failure consistent with our hypothesis that AGE accumulation is associated with reduced energy to failure at the tissue and structural levels. Use of two different AGE inhibitors will establish cause and effect, and may provide information about the mechanism of AGE accumulation, as the inhibitors act at different points of the reaction cycle.
Aim 3 will allow us to establish the relationship between AGE accumulation and altered mechanical properties in an estrogen-deficient animal model (ovariectomized rats), an established model for post-menopausal osteoporosis. Use of an AGE inhibitor will establish cause and effect between AGE accumulation and bone's material properties (toughness and normalized energy to failure) that may be more relevant to the post-menopausal situation than intact dogs. Acquisition of a new Skyscan 1172 micro-CT as part of an NIH infrastructure grant will allow us to assess changes in trabecular architecture to better characterize trabecular bone properties. It will also allow us to normalize the mechanical data by the plane of smallest BV/TV to prevent weighting by regions of bone with higher density that do not fail. Our work could help to explain the reason for the reduced toughness and normalized energy to failure found with bisphosphonate treatment, and to determine whether it is possible to prevent these changes in patients who are being treated with bisphosphonates. PUBLIC HEALTH NARRATIVE The objective of this proposal is to determine the role that collagen, and the accumulation of advanced glycation end-products, play in the mechanical properties of bone. This has relevance in understanding the fragility of bone that occurs in post-menopausal osteoporosis, and in Type II diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR047838-08
Application #
7847557
Study Section
Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
Sharrock, William J
Project Start
2001-07-01
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
8
Fiscal Year
2010
Total Cost
$328,878
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
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Hill Gallant, Kathleen M; Gallant, Maxime A; Brown, Drew M et al. (2014) Raloxifene prevents skeletal fragility in adult female Zucker Diabetic Sprague-Dawley rats. PLoS One 9:e108262
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Gallant, Maxime A; Brown, Drew M; Organ, Jason M et al. (2013) Reference-point indentation correlates with bone toughness assessed using whole-bone traditional mechanical testing. Bone 53:301-5
Green, J O; Diab, T; Allen, M R et al. (2012) Three years of alendronate treatment does not continue to decrease microstructural stresses and strains associated with trabecular microdamage initiation beyond those at 1 year. Osteoporos Int 23:2313-20

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