title: Matrix metalloproteinase-9-null mice are resistant to TGF-β-induced anterior subcapsular cataract formation.
abstract: Epithelial-mesenchymal transition (EMT) is associated with fibrotic diseases in the lens, such as anterior subcapsular cataract (ASC) formation. Often mediated by transforming growth factor (TGF)-β, EMT in the lens involves the transformation of lens epithelial cells into a multilayering of myofibroblasts, which manifest as plaques beneath the lens capsule. TGF-β-induced EMT and ASC have been associated with the up-regulation of two matrix metalloproteinases (MMPs): MMP-2 and MMP-9. The current study used MMP-2 and MMP-9 knockout (KO) mice to further determine their unique roles in TGF-β-induced ASC formation. Adenoviral injection of active TGF-β1 into the anterior chamber of all wild-type and MMP-2 KO mice led to the formation of distinct ASC plaques that were positive for α-smooth muscle actin, a marker of EMT. In contrast, only a small proportion of the MMP-9 KO eyes injected with adenovirus-expressing TGF-β1 exhibited ASC plaques. Isolated lens epithelial explants from wild-type and MMP-2 KO mice that were treated with TGF-β exhibited features indicative of EMT, whereas those from MMP-9 KO mice did not acquire a mesenchymal phenotype. MMP-9 KO mice were further bred onto a TGF-β1 transgenic mouse line that exhibits severe ASC formation, but shows a resistance to ASC formation in the absence of MMP-9. These findings suggest that MMP-9 expression is more critical than MMP-2 in mediating TGF-β-induced ASC formation.
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University Health Science Centre, Hamilton, Ontario, Canada.
authors.forename: Anna
authors.initials: A
authors.lastname: Korol
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University Health Science Centre, Hamilton, Ontario, Canada.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Pino
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University Health Science Centre, Hamilton, Ontario, Canada.
authors.forename: Dhruva
authors.initials: D
authors.lastname: Dwivedi
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University Health Science Centre, Hamilton, Ontario, Canada.
authors.forename: Jennifer V
authors.initials: JV
authors.lastname: Robertson
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University Health Science Centre, Hamilton, Ontario, Canada.
authors.forename: Paula A
authors.initials: PA
authors.lastname: Deschamps
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University Health Science Centre, Hamilton, Ontario, Canada. Electronic address: westmayj@mcmaster.ca.
authors.forename: Judith A
authors.initials: JA
authors.lastname: West-Mays
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D015820:Cadherins / Q000378:metabolism; D002386:Cataract / Q000139:chemically induced / Q000235:genetics*; D058750:Epithelial-Mesenchymal Transition; D007903:Lens Capsule, Crystalline / Q000473:pathology*; D020778:Matrix Metalloproteinase 2 / Q000235:genetics; D020780:Matrix Metalloproteinase 9 / Q000235:genetics*; D018345:Mice, Knockout; D008822:Mice, Transgenic; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*
chemical_list: C558396:Acta2 protein, mouse; D000199:Actins; D015820:Cadherins; D053773:Transforming Growth Factor beta1; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse