The role of glycoxidation on bone mineralization and matrix quality
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Authors
Stephen, Samuel, Joseph
Issue Date
2024-05
Type
Electronic thesis
Thesis
Thesis
Language
en_US
Keywords
Biomedical engineering
Alternative Title
Abstract
Type 2 diabetes (T2D) and obesity are prevalent conditions associated with heightened fracture risk despite patients exhibiting normal or elevated bone mineral density (BMD). BMD is a routinely used measurement that predicts fracture risk in osteoporosis, so the inability for BMD to accurately capture fracture risk in T2D and obesity suggests that the quality of bone is impaired rather than its quantity in these conditions. Thus, much effort has been directed to determine how bone quality, which contributes to bone strength independently of BMD, is perturbed in T2D and obesity. Chronic, low-grade inflammation is a common feature of T2D and obesity that subsequently promotes glycoxidation, a simultaneous glycation-oxidative stress process that generates advanced glycation end-products (AGEs) which can accumulate on proteins like collagen. Yet, little is known on the extent to which glycoxidation perturbs the extracellular matrix quality of bone. To this end, this research project aims to determine the role of glycoxidation on bone mineral and matrix quality, two nanoscale properties that contribute to bone’s fracture resistance. Inflammation, and consequently glycoxidation, is mediated by the receptor for advanced glycation end-products (RAGE). To investigate how glycoxidation impacts the matrix quality of bone, this project utilized an in vivo approach where wildtype and RAGE knockout mice were provided high-fat diet to induce obesity and inflammation. Results show that obesity induces glycoxidative AGE accrual in bone and was associated to altered mineral and matrix quality, while RAGE ablation ameliorated and preserved aspects of the bone matrix. The findings suggest that glycoxidation in obesity, via accrual of certain AGEs, is a process that can perturb the extracellular matrix of bone, working to change its quality and fracture resistance by extension.
To expand on the in vivo findings, an in vitro study was implemented where human bone was modified through the accrual of carboxymethyl-lysine (CML) and crosslinking AGEs and were later mineralized to elucidate the mechanism linking glycoxidation to altered bone mineralization and ultrastructural composition. Findings from this study demonstrated that AGE accumulation altered the molecular dynamics of collagen and mineral, and enhanced mineralization. These results augment the notion that glycoxidation impacts the quality of bone while also providing evidence of the nanoscale mechanism by which glycoxidation, via AGE accrual, perturbs the principal components of the bone matrix.
The impact of glycoxidation on citrate-mediated mineralization was investigated to elucidate another pathway by which oxidative stress can impair bone quality. It was discovered that glycoxidation interferes with citrate’s capacity to regulate mineralization, most likely by impairing the adsorption of citrate from solution into the organic network. Since citrate content, which is reflective of cellular metabolism, is influenced by oxidative stress, these findings provide novel evidence that glycoxidation may impair bone quality by altering the dynamics of citrate-mediated mineralization.
Finally, a mechanism explaining residual stress in bone mineral was explored to identify a pathway by which glycoxidation could impair the mechanical function of mineral through alterations to energy dissipation. It was discovered that epitaxial growth between unique crystals occurred in native bone, and organic matrix proteins were crucial for this type of growth modality. A model was designed to estimate the amount of stress caused by epitaxy in bone mineral, which can be further refined to elucidate how glycoxidation impairs bone’s mechanical properties by altering the residual stress state in the bone matrix.
Collectively, this research project demonstrates that the glycoxidation process can both directly and indirectly affect bone quality by altering the growth of mineral. This discovery greatly builds upon the established notion that oxidative stress in conditions like T2D and obesity impair bone quality by affecting the organic phase, and clearly demonstrates that the mineral phase and mineralization process can also be modified by oxidative stress products in the bone matrix. The findings from this work also provides a new way to better comprehend the reason behind the high fracture prevalence seen in T2D and obesity, which is critical for the development of diagnostic and preventative measures needed to mitigate fracture in these at-risk populations.
Description
May2024
School of Engineering
School of Engineering
Full Citation
Publisher
Rensselaer Polytechnic Institute, Troy, NY