Transforming Growth Factor–β Induces Extracellular Matrix Protein Cross-Linking Lysyl Oxidase (LOX) Genes in Human Trabecular Meshwork Cells

Abstract

Both Smad and non-Smad signaling pathways are involved in TGFβ-mediated LOX induction, suggesting complex regulation of these important extracellular matrix cross-linking enzymes. Increased LOX activity may be at least partially responsible for TGFβ-mediated IOP elevation and increased aqueous humor outflow resistance.

Fibroblast-specific inhibition of TGF-β1 signaling attenuates lung and tumor fibrosis

“…Because of the striking inhibition of Snail1 expression by several trihydroxyphenolic compounds ( Figure 1H and Supplemental Figure 1B), as well as the altered collagen cross-linking structure in primary 344SQ tumors ( Figure 2I), we explored the hypothesis that lysyl oxidase-like 2 (LOXL2) was their target. LOXL2 has previously been linked to Snail1 accumulation in tumor cells (30), and its expression is potently induced by both hypoxia and TGF-β1 (31,32). LOXL2, like all mammalian copper-dependent LOX enzymes, utilizes an intrinsically generated quinone, termed LTQ, to mediate oxidation Smad activation and Snail1 induction ( Figure 4F and Supplemental Figure 5, D-F).…”

Estradiol plays a role in regulating the expression of lysyl oxidase family genes in mouse urogenital tissues and human Ishikawa cells

“…The TGF-β signaling pathway has been shown to play an important role in many biological functions including the regulation of the extracellular matrix components and enzymes (Herpin et al, 2004). The TGF-β signaling pathway can regulate the amount and activity of the LOX family (LOX, LOXL1 to LOXL4) in human trabecular meshwork cells (Sethi et al, 2011). All five LOX family members can be upregulated by TGF-β1 in anterior cruciate ligament and medial collateral ligament fibroblasts after mechanical injury in humans (Xie et al, 2013).…”

“…We examined the expression of LOX family genes in the urogenital tissues of accelerated ovarian aging mice and Ishikawa cells following treatment with E2. Previous studies have shown that TGF-β family members may regulate LOX family genes (Sethi et al, 2011) and that E2 could significantly increase the expression of TGF-β family members in the uterus and vagina of mice (Takahashi et al, 1994). Thus, a preliminary investigation of the role of the TGF-β signal pathway in the relationship between E2 and the LOX family genes was included.…”

Common and Rare Genetic Risk Factors for Glaucoma

“…Several of the genes contributing to early-onset glaucoma (MYOC, LTBP2, COL18A1) and adult-onset glaucoma (LOXL1) have important roles in extracellular matrix (Ueda et al 2002;Ali et al 2009;Sethi et al 2011;Wiggs et al 2013b), and three important genes related to CCT impact extracellular matrix (Lu et al 2013). Further investigation of genes shown to contribute to extracellular processes in ocular tissues relevant to glaucoma could be of interest.…”

“…TGF-b I and TGF-b II appear to have important roles in optic nerve degeneration (Zode et al 2009;Fuchshofer 2011) as well as trabecular meshwork function (Sethi et al 2011;Fuchshofer 2012). LTPB2 (associated with congenital glaucoma and anterior segment dysgenesis) and CDKN2BAS (associated with POAG, NTG) are part of the overall TGF-b signaling pathway.…”