Calcium-Signalling in Human Glaucoma Lamina Cribrosa Myofibroblasts

Abstract

Glaucoma is one of the most common causes of treatable visual impairment in the developed world, affecting approximately 64 million people worldwide, some of whom will be bilaterally blind from irreversible optic nerve damage. The optic nerve head is a key site of damage in glaucoma where there is fibrosis of the connective tissue in the lamina cribrosa (LC) extracellular matrix. As a ubiquitous second messenger, calcium (Ca2+) can interact with various cellular proteins to regulate multiple physiological processes and contribute to a wide range of diseases, including cancer, fibrosis, and glaucoma. Our research has shown evidence of oxidative stress, mitochondrial dysfunction, an elevated expression of Ca2+ entry channels, Ca2+-dependent pumps and exchangers, and an abnormal rise in cytosolic Ca2+ in human glaucomatous LC fibroblast cells. We have evidence that this increase is dependent on Ca2+ entry channels located in the plasma membrane, and its release is from internal stores in the endoplasmic reticulum (ER), as well as from the mitochondria. Here, we summarize some of the molecular Ca2+-dependent mechanisms related to this abnormal Ca2+-signalling in human glaucoma LC cells, with a view toward identifying potential therapeutic targets for ongoing optic neuropathy.

Genome-wide RNA sequencing of ocular fibroblasts from glaucomatous and normal eyes: Implications for glaucoma management

“…Myofibroblasts may originate from epithelial cells (via a process called EMT), endothelial cells (via EndMT), regular fibroblasts and other cells [ 34 , 35 ]. Myofibroblasts and corresponding biological processes such as EMT have been reported to play a role in the context of glaucoma, for instance in retinal pigment epithelial cells [ 36 ], lamina cribrosa cells [ 37 ] and trabecular meshwork cells [ 38 , 39 ]. In keeping with our results, Tenon’s ocular fibroblasts from glaucomatous patients were reported to show signs of a myofibroblast phenotype by determining differential expression of a predefined panel of 10 genes [ 16 ].…”

Association between dietary calcium, potassium, and magnesium consumption and glaucoma

“…In our study, Ca consumption reached the recommended level was associated with a decreased risk of glaucoma. Ca 2+ is a second messenger that interacts with various cellular proteins and regulates multiple physiological processes that contribute to diseases including cancer, fibrosis, and glaucoma [ 34 ]. The intracellular concentration of Ca 2+ is low with a high inwardly directed concentration [ 35 ], and there are various pathways of cellular Ca regulation both extracellularly and intracellularly [ 36 ].…”

“…Study demonstrated that Ca dysregulation results in the wild-type myocilin misfolding initially and may further contribute broadly to glaucoma-associated endoplasmic reticulum stress [ 44 ]. Therefore, we postulated that enough dietary Ca intake could supplement Ca loss in the cytoplasm after excessive Ca 2+ entered mitochondria during the progression of glaucoma to maintain Ca 2+ homeostasis in lamina cribrosa cells [ 34 ].…”