BMP and Activin Membrane Bound Inhibitor Regulates the Extracellular Matrix in the Trabecular Meshwork

PURPOSE. The trabecular meshwork (TM) has an important role in the regulation of aqueous humor outflow and IOP. Regulation of the extracellular matrix (ECM) by TGF beta 2 has been studied extensively. Bone morphogenetic protein (BMP) and activin membrane-bound inhibitor (BAMBI) has been shown to inhibit or modulate TGF beta 2 signaling. We investigate the role of TGF beta 2 and BAMBI in the regulation of TM ECM and ocular hypertension. METHODS. Mouse TM (MTM) cells were isolated from B6; 129S1-Bambi(tm1Jian)/J flox mice, characterized for TGF beta 2 and dexamethasone (DEX)-induced expression of fibronectin, collagen-1, collagen-4, laminin, alpha-smooth muscle actin, cross-linked actin networks (CLANs) formation, and DEX-induced myocilin (MYOC) expression. MTM cells were transduced with Ad5.GFP to identify transduction efficiency. MTM cells and mouse eyes were transduced with Ad5. Null, Ad5. Cre, Ad5.TGF beta 2, or Ad5.TGF beta 2 + Ad5.Cre to evaluate the effect on ECM production, IOP, and outflow facility. RESULTS. MTM cells express TM markers and respond to DEX and TGF beta 2. Ad5. GFP at 100 MOI had the highest transduction efficiency. Bambi knockdown by Ad5.Cre and Ad5.TGF beta 2 increased fibronectin, collagen-1, and collagen-4 in TM cells in culture and tissue. Ad5.Cre, Ad5.TGF beta 2, and Ad5.TGF beta 2 + Ad5. Cre each significantly induced ocular hypertension and lowered aqueous humor outflow facility in transduced eyes. CONCLUSIONS. We show for the first time to our knowledge that knockdown of Bambi alters ECM expression in cultured cells and mouse TM, reduces outflow facility, and causes ocular hypertension. These data provide a novel insight into the development of glaucomatous TM damage and identify BAMBI as an important regulator of TM ECM and ocular hypertension.