Matrix metalloproteinase inhibitors suppress transforming growth factor-beta-induced subcapsular cataract formation.
The pleotropic morphogen transforming growth factor-beta (TGFbeta) plays an important role in the development of fibrotic pathologies, including anterior subcapsular cataracts (ASCs). ASC formation involves increased proliferation and transition of lens epithelial cells into myofibroblasts, through epithelial-mesenchymal transformation that results in opaque plaques beneath the lens capsule. In this study, we used a previously established TGFbeta-induced rat cataract model to explore the role of matrix metalloproteinases (MMPs) in ASC formation. Treatment of excised rat lenses with TGFbeta resulted in enhanced secretion of MMP-2 and MMP-9. Importantly, co-treatment with two different MMP inhibitors (MMPIs), the broad spectrum inhibitor GM6001 and an MMP-2/9-specific inhibitor, suppressed TGFbeta-induced ASC changes, including the epithelial-mesenchymal transformation of lens epithelial cells. Using an anti-E-cadherin antibody, we revealed that conditioned media from lenses treated with TGFbeta contained a 72-kd E-cadherin fragment, indicative of E-cadherin shedding. This was accompanied by attenuated levels of E-cadherin mRNA. Conditioned media from lenses co-treated with TGFbeta and MMPIs exhibited attenuated levels of the E-cadherin fragment compared with those from TGFbeta-treated lenses. Together, these findings demonstrate that TGFbeta-induced E-cadherin shedding in the lens is mediated by MMPs and that suppression of this phenomenon might explain the mechanism by which MMPIs inhibit ASC plaque formation.
Dwivedi
Dhruva J
DJ
Department of Pathology and Molecular Medicine, McMaster University, HSC 1R10, Hamilton, ON, Canada L8N3Z5.
Pino
Giuseppe
G
Banh
Alice
A
Nathu
Zahra
Z
Howchin
Derek
D
Margetts
Peter
P
Sivak
Jacob G
JG
West-Mays
Judith A
JA
D000818:Animals; D015153:Blotting, Western; D015820:Cadherins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D002386:Cataract / Q000188:drug therapy* / Q000209:etiology; D017077:Culture Media, Conditioned; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015870:Gene Expression; D007150:Immunohistochemistry; D007834:Lasers; D007908:Lens, Crystalline / Q000187:drug effects* / Q000473:pathology; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism* / Q000494:pharmacology; D042282:Microdissection; D009924:Organ Culture Techniques; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000494:pharmacology
D015820:Cadherins; D017077:Culture Media, Conditioned; D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D016212:Transforming Growth Factor beta; D020782:Matrix Metalloproteinases