R01AG075654

Effects of Advanced Glycation Endproducts on Type 2 Diabetic and Fragility Fractures - Abstract

Bone fractures contribute significantly to healthcare costs, affecting the quality of life. Clinically, fracture risk can be predicted by Dual X-ray Absorptiometry (DXA) or the Fracture Risk Assessment (FRAX) tool. However, in Type 2 Diabetes (T2D) patients, who exhibit high bone mineral density (BMD), both tools fail to accurately predict fracture risk, leading to a significant increase in fragility fractures among diabetic individuals. Therefore, there is a need to investigate how modifications in collagen and other organic components in bone can predict diabetic fractures.

Pentosidine (PEN), a fluorescent Advanced Glycation Endproduct (AGE) that forms in bone through the reaction between sugars and proteins, is the only established marker of bone fragility. However, it does not consistently predict T2D and fragility fractures. In this study, we demonstrate, for the first time in bone, the presence of carboxymethyl-lysine (CML), a non-fluorescent glycoxidative AGE, and present a technique to measure it. We show that CML forms abundantly in bone and is highly correlated with the loss of bone toughness. Furthermore, we demonstrate that, unlike other AGEs, CML is upregulated by more than 60% in T2D human bone compared to their age-matched controls. We then provide evidence that CML promotes the formation and growth of additional hydroxyapatite (HA) crystals, similar to the human T2D condition, and forms a 'molecular link' between the organic and inorganic components of bone (collagen-HA interface), impairing bone quality.

Our overall hypothesis is that CML is a 'new and relevant' biomarker of T2D fracture that captures the effects of both hyperglycemia and oxidative stress in bone, explaining the susceptibility of bone to fracture in T2D. Using an obese and a non-obese mouse model of T2D that mimic both the causality and impact of human T2D on bone, we provide evidence that T2D increases AGEs, with CML explaining bone fragility. Similarly, using data from the Health, Aging, and Body Composition (ABC) study, we show that higher serum CML levels are associated with an increased risk of incident clinical fractures in T2D, independent of BMD.

Thus, our overall goal is to establish CML as a new and relevant biomarker of bone fragility and determine how it contributes to bone fragility in T2D. We will pursue three aims using in vitro models, ex vivo human cadaveric tissue, in vivo mouse models of obese and non-obese T2D, and existing data from the Health ABC study:

Aim 1: Establish the necessary conditions for enhanced formation of CML over other AGEs and determine the mechanism(s) by which it reduces energy dissipation in bone.
Aim 2: Determine the contribution of CML and other AGEs to alterations in bone matrix and energy dissipation in human T2D vertebrae and cortical and cancellous bone from hip fracture patients.
Aim 3: Validate CML as a biomarker of T2D bone fragility and establish its association with hyperglycemia and oxidative stress.

Our findings will provide a new understanding of the mechanism and effects of CML and other AGEs on bone fractures, leading to new strategies to predict, manage, and mitigate T2D and fragility fractures.

Rensselaer Polytechnic Institute

TO ENCOURAGE BIOMEDICAL, SOCIAL, AND BEHAVIORAL RESEARCH AND RESEARCH TRAINING DIRECTED TOWARD GREATER UNDERSTANDING OF THE AGING PROCESS AND THE DISEASES, SPECIAL PROBLEMS, AND NEEDS OF PEOPLE AS THEY AGE. THE NATIONAL INSTITUTE ON AGING HAS ESTABLISHED PROGRAMS TO PURSUE THESE GOALS. THE DIVISION OF AGING BIOLOGY EMPHASIZES UNDERSTANDING THE BASIC BIOLOGICAL PROCESSES OF AGING. THE DIVISION OF GERIATRICS AND CLINICAL GERONTOLOGY SUPPORTS RESEARCH TO IMPROVE THE ABILITIES OF HEALTH CARE PRACTITIONERS TO RESPOND TO THE DISEASES AND OTHER CLINICAL PROBLEMS OF OLDER PEOPLE. THE DIVISION OF BEHAVIORAL AND SOCIAL RESEARCH SUPPORTS RESEARCH THAT WILL LEAD TO GREATER UNDERSTANDING OF THE SOCIAL, CULTURAL, ECONOMIC AND PSYCHOLOGICAL FACTORS THAT AFFECT BOTH THE PROCESS OF GROWING OLD AND THE PLACE OF OLDER PEOPLE IN SOCIETY. THE DIVISION OF NEUROSCIENCE FOSTERS RESEARCH CONCERNED WITH THE AGE-RELATED CHANGES IN THE NERVOUS SYSTEM AS WELL AS THE RELATED SENSORY, PERCEPTUAL, AND COGNITIVE PROCESSES ASSOCIATED WITH AGING AND HAS A SPECIAL EMPHASIS ON ALZHEIMER'S DISEASE. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM; TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT; TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT; AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS; TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS; TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT; AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.866 - Aging Research

National Institute on Aging (NIA) [HHS - NIH]

Troy, New York 121803522 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 411% from $598,797 to $3,062,017.