The Involvement of HYBID in the Regulation of Intraocular Pressure and Extracellular Matrix Accumulation in the...

Increased accumulation of extracellular matrix (ECM) in the trabecular meshwork (TM) causes a rise in intraocular pressure (IOP), which is a primary risk factor for glaucoma. Hyaluronan (HA) is essential for forming the ECM network, but it is unclear whether HA metabolism plays a role in IOP control. In this study, we focused on the hyaluronan-binding protein involved in hyaluronan depolymerization (HYBID, also referred to as cell migration inducing hyaluronidase 1 (CEMIP)/KIAA1199), which is an HA-degrading enzyme. Hybid knockout (KO) mice exhibited IOP elevation [IOP on average +2.14 mmHg at 7 weeks old, +1.54 mmHg at 8 weeks old vs. IOP of wildtype (WT) mice]. In addition, fibronectin and HA accumulated in the TM of Hybid KO mice. In cultured human TM cells (HTMCs), HYBID knockdown with HYBID siRNA increased HA and fibronectin protein but the expression of fibronectin mRNA was not altered. In addition, in HYBID knockdown HTMCs, matrix metalloproteinase (MMP)-1 and tissue inhibitor of metalloproteinase (TIMP) 3 were increased and MMP-9 was decreased. These results indicated that HYBID knockdown did not contribute to fibronectin production but inhibited ECM degradation through decreased MMP-9 expression and increased TIMP3 expression, leading to reduced MMP-2 and MMP-9 activity. These findings may offer new perspectives on the underlying mechanisms of glaucoma associated with fibrosis and potentially contribute to the development of novel glaucoma therapeutics.