Corneal Stiffness and Collagen Cross-Linking Proteins in Glaucoma: Potential for Novel Therapeutic Strategy

Abstract

Biomechanical properties of the cornea have recently emerged as clinically useful in risk assessment of diagnosing glaucoma and predicting disease progression. Corneal hysteresis (CH) is a dynamic tool, which measures viscoelasticity of the cornea. It represents the overall deformability of the cornea, and reduces significantly with age. Low CH has also been associated with optic nerve damage and progression of visual field loss in glaucoma. The extracellular matrix (ECM) constituents of the cornea, trabecular meshwork (TM), sclera, and lamina cribrosa (LC) are similar, as they are predominantly made of fibrillar collagen. This suggests that biomechanical changes in the cornea may also reflect optic nerve compliance in glaucomatous optic neuropathy, and in the known increase of TM tissue stiffness in glaucoma. Increased collagen cross-linking contributes to tissue stiffening throughout the body, which is observed in normal aging and occurs at an accelerated rate in systemic conditions such as fibrotic and cardiovascular diseases, cancer, and glaucoma. We reviewed 3 ECM cross-linking proteins that may have a potential role in the disease process of increased tissue stiffness in glaucoma, including lysyl oxidase (LOX)/lysyl oxidase-like 1 (LOXL1), tissue transglutaminase (TG2), and advanced glycation end products. We also report elevated messenger RNA (mRNA) levels of LOX and TG2 in glaucoma LC cells to support our proposed theory that increased levels of cross-linking proteins in glaucoma play a role in LC tissue stiffness. We highlight areas of research that are needed to better understand the role of cross-linking in glaucoma pathogenesis, leading potentially to a novel therapeutic strategy.

Material properties and effect of preconditioning of human sclera, optic nerve, and optic nerve sheath

“…The sclera has even been characterized by optomechanical birefringence (Shin et al 2018 ). While there have been extensive investigations of anterior ocular tissues such as cornea (Carnell and Vito 1992 ; Liu and He 2009 ; Rahman et al 2020 ), sclera (Coudrillier et al 2013 ; Downs et al 2005 ; Eilaghi et al 2010 ; Elsheikh et al 2010b ; Pijanka et al 2012 ; Wollensak and Spoerl 2004 ), and the lamina cribrosa (LC) of the optic disk (Brazile et al 2018 ; Coudrillier et al 2016 ; Feola et al 2017 ; Midgett et al 2020 ; Sigal et al 2014 ), the biomechanical properties of tissues posterior to the globe have been comparatively neglected. Biomechanical properties of the bovine ON have been reported (Shin et al 2017 ), but human ON data are currently lacking, despite the presence of abundant connective tissue around and within the human ON that distinguishes it from other neural tissue such as brain (Karim et al 2004 ).…”

Advanced Glycation End Products Are Retained in Decellularized Muscle Matrix Derived from Aged Skeletal Muscle

“…Collagen cross-linking significantly regulates the mechanical properties of tissues [90]. In old age, skeletal muscle stiffens and dysregulates the satellite cell niche, abrogating regeneration [19,20].…”

Looking into the future: Gene and cell therapies for glaucoma

“…Transgene expression can be targeted to the cornea by intrastromal, intracameral, or subconjunctival injection, as well as topical eye drop application following removal of the corneal epithelium 240 . Based on the available technologies, corneal gene therapy could be considered an additional possible tool to decrease an individual's susceptibility to glaucomatous optic nerve damage 241 …”