Glaucoma is a progressive optic neuropathy frequently associated with elevated intraocular pressure (IOP) and extracellular matrix (ECM) remodeling at the optic nerve head and in the trabecular meshwork (TM). The pathogenesis is multifactorial and complex, but many recent studies have suggested that transforming growth factor-β (TGF-β) plays a major role in the process. Patients with glaucoma have elevated levels of TGF-β2 in their aqueous humor, and TGF-β has been shown to increase TM ECM production. The bone morphogenetic proteins (BMP) are other members of the TGF-β superfamily of growth factors that modify TGF-β signaling in several different tissues including TM. For instance, BMP-4 and BMP-7 serve to prevent ECM deposition and strongly antagonize the fibrogenic actions of TGF-β2 on human TM cells. Latent transforming growth factor (TGF)-beta binding protein 2 (LTBP2) is an ECM protein that has previously been shown to be the cause of primary congenital glaucoma (PCG) and other disorders that often manifest as secondary glaucoma. It was suggested that LTBP2 may be involved in the disease process via its effects on TGF-β activation. On the other hands LTBP2 is an ECM microfibril protein, and defects in the ECM of the TM may affect facility of aqueous fluid outflow resulting in increased IOP and glaucoma. In this study we investigated the role of LTBP2 in TGF-β signaling pathway activation and ECM genes expression in TM cells.

Western immunoblot analysis of proteins downstream the TGF-β and BMP signaling pathways was used to evaluate the effects of LTBP2 knock down on the both pathways in TM cells. Real time PCR analysis was used to determine the expression of ECM related genes in absence of LTBP2 expression.

LTBP2 knock down significantly increased activation of TGF-? signaling pathway, concomitant with decreased activation of BMP pathway. LTBP2 knock down also increased expression of some of ECM genes in TM cells.

LTBP2 mutations in glaucoma patients may be relevant to TGF-β signaling pathway activation and increase in ECM proteins production in glaucomatous tissues such as TM, leading to decreased aqueous humor outflow.