Abstract
Diabetes mellitus is a widespread metabolic disorder linked to numerous systemic complications, including adverse effects on skeletal health, such as increased bone fragility and fracture risk. Emerging evidence suggests that high glucose may disrupt the extracellular matrix (ECM) of bone, potentially altering its composition and organization. Collagen, the primary organic component of the ECM, is critical for maintaining structural integrity and biomechanical properties. However, definitive evidence and a comprehensive understanding of the molecular mechanisms through which high glucose impacts the ECM and collagen remain elusive. This study employed an ex vivo embryonic chicken femur model to investigate the effects of high glucose on the collagenous matrix. A comprehensive approach integrating histological evaluation, histomorphometry, ATR-FTIR spectroscopy, and proteomics was adopted to unravel structural, biochemical, and molecular changes in the ECM. Histomorphometric analysis revealed disrupted collagen fibril architecture, characterized by altered fibril diameter, alignment, and spatial organization. ATR-FTIR spectroscopy highlighted biochemical modifications, including non-enzymatic glycation that impaired collagen crosslinking and reduced matrix integrity. Proteomic profiling unveiled significant alterations in ECM composition and function, including downregulation of key collagen crosslinking enzymes and upregulation of inflammatory and coagulation pathways. High glucose profoundly disrupts the collagenous matrix of bone, weakening its structural integrity and organization. These findings emphasize the critical impact of high glucose environments on extracellular matrix composition and bone quality, offering insights into the mechanisms behind diabetic bone fragility and guiding future research toward targeted therapeutic strategies.