Due to the range of LOX biological functions, abnormalities of LOX expression underlie the development of a number of pathological processes related with an imbalance in ECM synthesis/degradation. These include connective tissue fibrotic disorders of the heart (myocardial fibrosis), vasculature (arterial fibrosis), lungs (pulmonary fibrosis), skin (keloids, and scleroderma), kidney (nephritis), liver (liver stiffness preceding liver fibrosis), mouth (gingival atrophy), and colon (intestinal fibrotic disease). LOX is also associated with diseases such as rheumatoid arthritis, systemic sclerosis, Alzheimer’s disease, and several stages of breast cancer. (Rodriguez et al., 2008
LOX is expressed in several ocular tissues, and the following diseases of the eye have been linked with LOX:
Keratoconus is a corneal degeneration in which the extracellular matrix of the cornea loses its integrity, slowly changing from the normal round shape to a cone shape. One study reported that corneal LOX mRNA expression was significantly lower in keratoconus patients when compared to their age-matched controls. Another study showed that reducing copper levels in tears results in keratoconus in an animal model. Copper is an essential cofactor for LOX activity.
- Diabetic retinopathy (DR)
There are a number of reports of lower expression of LOX co-factors in DR retina samples and lower LOX cross-linking activity in vitreous samples of patients with DR. However, the effect of high glucose on LOX expression and enzymatic activity in cultured human retinal endothelial cells is less clear, with conflicting evidence suggesting either increased or decreased LOX expression. Although discrepant, these studies indicate a potential involvement of LOX in the observed DR phenotype.
- Rhegmatogenous retinal detachment (RRD)
RRD occurs when a tear in the retina leads to fluid accumulation beneath the retina that causes a separation of the neurosensory retina from its underlying RPE. Vitreous samples of normal vs. RRD patients revealed lower LOX activity in RRD vitreous samples, although the mechanisms of LOX down-regulation and RRD are unknown.
- Primary open angle glaucoma (POAG)
There are no direct reports of dysregulated LOX expression in primary open angle glaucoma. However, we recently reported that transforming growth factor beta 1–3 (TGFβ1–3) induce LOX and LOXL1-4 in human trabecular meshwork (TM) cells (Sethi et al. 2011
). Both TGFβ1 and -2 have previously been reported to be profibrotic in the TM. There is evidence for the involvement of TGFβ2 in POAG and TGFβ1 in pseudoexfoliation (PEX) glaucoma. We also observed that gremlin, another profibrotic molecule that is elevated in glaucoma TM cells, induces expression of LOX genes in cultured human TM cells (unpublished data). Taken together, these data suggest a possible role for LOX in POAG and PEX pathogenesis. Another member of the LOX gene family, LOXL1, which is induced by TGFβ1, is associated with increased risk of developing PEX glaucoma and may play a role in the pathogenesis of PEX.