Intraocular pressure reduction attenuates form-deprivation myopia by modulating scleral extracellular matrix remodeling via the TGF-β1/Smad signaling pathway.

OBJECTIVE: This study aimed to investigate whether intraocular pressure (IOP) reduction achieved separately using two mechanistically distinct IOP-lowering agents, brinzolamide and latanoprost, attenuates form-deprivation myopia (FDM) by regulating scleral extracellular matrix (ECM) dynamics and to elucidate the underlying involvement of the TGF-β1/Smad signaling pathway. METHODS: We established a murine model of unilateral FDM with the contralateral untreated eye serving as an intra-individual control and assessed key ocular parameters, including IOP, axial length (AL), and refractive error (RE). Scleral tissues were subjected to hematoxylin and eosin (H&E) staining and Western blot analysis. Primary human scleral fibroblasts (HSFs) were exposed to hypoxia to mimic myopic stress, and cell viability, proliferation, and apoptosis were evaluated using Cell Counting Kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU), flow cytometry, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays. Protein expression of ECM-related markers and key components of the TGF-β1/Smad pathway was analyzed by Western blot. The functional role of the TGF-β1/Smad axis was further examined using the selective inhibitor LY2109761. RESULTS: IOP reduction induced separately by brinzolamide and latanoprost (via distinct mechanisms of action) effectively attenuated IOP elevation, axial elongation, and myopic shift in FDM mice, accompanied by preserved scleral architecture and normalized expression of type I collagen, matrix metalloproteinase-2 (MMP2), tissue inhibitor of metalloproteinase-2 (TIMP-2), and α-smooth muscle actin (α-SMA). In HSFs under hypoxia, both IOP-lowering agents exerted consistent protective effects, restoring cell viability and proliferation, suppressed apoptosis, and reversed hypoxia-induced ECM dysregulation. These protective effects were associated with upregulation of TGF-β1, phosphorylated Smad2 (p-Smad2), and phosphorylated Smad3 (p-Smad3) in both in vivo and in vitro models. Co-treatment with LY2109761 completely abolished the beneficial effects of IOP reduction on ocular biometry, scleral structure, cellular function, and ECM protein expression. CONCLUSION: Intraocular pressure reduction achieved separately via two mechanistically distinct pharmacological approaches mitigates FDM by preserving scleral integrity through modulation of ECM remodeling, an effect mediated via activation of the TGF-β1/Smad signaling pathway.