Extragonadal role of FSH in regulating corneal homeostasis in Keratoconus

Keratoconus (KC) is a multifactorial, progressive, ectatic disease of the cornea, which often manifests during puberty. The clinical phenotype includes progressive loss of stromal collagen, with emerging evidence indicating inflammation contributes to the disease pathology. In this study, we investigated the extragonadal role of follicle-stimulating hormone (FSH) in corneal stromal collagen degradation and inflammation. Using a 3D collagen hydrogel system, co-culture models, and patient-derived tears, we found the following: FSH levels were low in KC patients; FSH supplementation inhibited MAP kinase signaling, leading to decreased MMP2 activity and increased collagen accumulation; FSH increased pro-inflammatory cytokine secretion, driving macrophage polarization, migration, and tunneling nanotube formation; FSH regulated the HDAC1-miR-29b feedback loop in chromatin immunoprecipitation and overexpression studies; Gene ontology linked FSH to leukocyte adhesion and extravasation; and Motif analysis identified NF-Y as a possible HDAC1-interacting partner. Collectively, FSH plays a dual role in keratoconus by regulating collagen accumulation through the MAP Kinase-MMP2 axis and inflammation through the HDAC1-miR-29b pathway. Human patient tears, 3D corneal hydrogel model, and co-culture model were used to identify the role of FSH in the cornea. We found that the FSH played a dual role in the regulation of corneal extracellular matrix remodeling and inflammation.