Mechanisms of Collagen Crosslinking in Diabetes and Keratoconus

Abstract

Collagen crosslinking provides the mechanical strength required for physiological maintenance of the extracellular matrix in most tissues in the human body, including the cornea. Aging and diabetes mellitus (DM) are processes that are both associated with increased collagen crosslinking that leads to increased corneal rigidity. By contrast, keratoconus (KC) is a corneal thinning disease associated with decreased mechanical stiffness leading to ectasia of the central cornea. Studies have suggested that crosslinking mediated by reactive advanced glycation end products during DM may protect the cornea from KC development. Parallel to this hypothesis, riboflavin-mediated photoreactive corneal crosslinking has been proposed as a therapeutic option to halt the progression of corneal thinning by inducing intra- and intermolecular crosslink formation within the collagen fibrils of the stroma, leading to stabilization of the disease. Here, we review the pathobiology of DM and KC in the context of corneal structure, the epidemiology behind the inverse correlation of DM and KC development, and the chemical mechanisms of lysyl oxidase-mediated crosslinking, advanced glycation end product-mediated crosslinking, and photoreactive riboflavin-mediated corneal crosslinking. The goal of this review is to define the biological and chemical pathways important in physiological and pathological processes related to collagen crosslinking in DM and KC.

An Inducible Model for Unraveling the Effects of Advanced Glycation End-Product Accumulation in Aging Connective Tissues

“…While it is still not completely understood the specific sites of AGEs in collagen, previously it has been suggested that glycations from ribose that form AGEs primarily target lysine, arginine, and histidine. 35,[80][81][82] While photo-initiated riboflavin can react with lysine and arginine, these amine groups have been shown to play a smaller role in riboflavin crosslinking. 83 Instead, riboflavin crosslinking has been suggested to be more dependent on carbonyl groups, such as hydroxyproline, hydroxylysine, tyrosine, and threonine.…”

Regenerative and Antioxidant Properties of Autologous Platelet-Rich Plasma Can Reserve the Aging Process of the Cornea in the Rat Model

“…Descemet's membrane (DM) is the basement membrane of the corneal endothelium composed predominately of type VIII collagen. It plays a crucial role in endothelial cell differentiation and proliferation and structural integrity [ 40 ]. The corneal endothelial layer has an important function to maintain corneal transparency.…”

Enhancement of collagen 1 expression by prostaglandin F2α agonists is pivotally involved in the pathogenesis of deepening of the upper eyelid sulcus

“…The synthesis of COL1 is known to be a complex process, and includes a series of post-translational modifications (Chun, 2012). Among these, intra-and extra-cellular post-translational modifications of specific lysine residues mediated by LOX are pivotal in forming covalent COL cross-linking for fibrillogenesis and the stability of fibrils (McKay, Priyadarsini & Karamichos, 2019). These maturation processes of COL cross-linkages varies from tissue to tissue, and are most likely related to the physiological states of different tissues (Wei, Gao, Wu, Qin & Yuan, 2020).…”