Estrogen-mediated corneal collagen degradation in keratoconus

Keratoconus (KC) is characterized by corneal thinning due to pathologic degradation of corneal stromal collagen. This study investigates the role of β-estradiol in corneal collagen degradation using both tear fluid samples from KC and non-KC patients and in vitro models (co-culture and 3D collagen hydrogel model). In tear fluids, we observed sex-specific differences in matrix metalloproteinase (MMP) activity, secretory phospholipase A2 (PLA2G2A) levels, and in cytokine profiles, including interleukin (IL-) 2, 3, 5, 6, 8, 11, 13, 15, 19, 24, 27, 31, and 32 tumor necrosis factor (TNF-α), angiopoietin 2, vitamin D binding protein, insulin growth factor binding proteins (IGFBP3), vascular endothelial growth factor (VEGF), and receptor for advanced glycation end product (RAGE). Our model showed that both corneal epithelium and fibroblasts synthesize their own estrogen, and β-estradiol treatment via p38 MAP kinase pathway regulates MMP2-mediated collagen fiber degradation. p38 MAP kinase inhibitor SB202190 significantly reduced β-estradiol-induced MMP activity and collagen breakdown, as well as cytokine regulation suggesting a potential therapeutic approach.