The role of collagen crosslinks in ageing and diabetes - the good, the bad, and the ugly

The non-enzymatic reaction of proteins with glucose (glycation) is a topic of rapidly growing importance in human health and medicine. There is increasing evidence that this reaction plays a central role in ageing and disease of connective tissues. Of particular interest are changes in type-I collagens, long-lived proteins that form the mechanical backbone of connective tissues in nearly every human organ. Despite considerable correlative evidence relating extracellular matrix (ECM) glycation to disease, little is known of how ECM modification by glucose impacts matrix mechanics and damage, cell-matrix interactions, and matrix turnover during aging. More daunting is to understand how these factors interact to cumulatively affect local repair of matrix damage, progression of tissue disease, or systemic health and longevity. This focused review will summarize what is currently known regarding collagen glycation as a potential driver of connective tissue disease. We concentrate attention on tendon as an affected connective tissue with large clinical relevance, and as a tissue that can serve as a useful model tissue for investigation into glycation as a potentially critical player in tissue fibrosis related to ageing and diabetes.