May 2008
Volume 49, Issue 13
ARVO Annual Meeting Abstract  |   May 2008
Mice Lacking MMP-9 Exhibit Delayed Onset of TGFβ1-Stimulated ASC Formation
Author Affiliations & Notes
  • G. Pino
    Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
  • M. E. Fini
    Bascom Palmer Eye Institute, University of Miami, Miller School of Medicine, Miami, Florida
  • J. A. West-Mays
    Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
  • Footnotes
    Commercial Relationships  G. Pino, None; M.E. Fini, None; J.A. West-Mays, None.
  • Footnotes
    Support  NIH EY017146 (JWM), CIHR (79462)
Investigative Ophthalmology & Visual Science May 2008, Vol.49, 3728. doi:
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      G. Pino, M. E. Fini, J. A. West-Mays; Mice Lacking MMP-9 Exhibit Delayed Onset of TGFβ1-Stimulated ASC Formation. Invest. Ophthalmol. Vis. Sci. 2008;49(13):3728. doi:

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      © ARVO (1962-2015); The Authors (2016-present)

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Purpose: : Sustained lens specific-expression of active transforming growth factor β-1 (TGFβ1) in transgenic mice or transient adenoviral delivery of active TGFβ1 induces the formation of fibrotic plaques similar to that observed in anterior subcapsular cataracts (ASC) in humans. Through inhibition studies our lab has previously demonstrated that matrix metalloproteinases (MMPs), specifically MMP-2 and -9, are important in ASC progression. Furthermore, we have previously demonstrated that employment of the adenoviral model in conjunction with MMP-9 germ-line knockout mice (MMP-9-/-) results in the suppression of ASC. Therefore, we investigated the effect of sustained lens specific TGFβ expression on ASC formation in mice lacking MMP-9.

Methods: : TGFβ1 transgenic mice were bred with MMP-9 heterozygous mice to generate mice with the following genotypes: TGFβ1/MMP-9-/- (null), TGFβ1/MMP-9+/+ and non-transgenic/MMP-9+/+ (controls). Animals were sacrificed at 4, 8 and 11 weeks. The eyes were then dissected, fixed for histology and stained with Masson’s Trichrome or used for immunohistochemical localization of alpha-smooth muscle actin (α-SMA).

Results: : All TGFβ1/MMP-9+/+ mice at 4 weeks (n=5), 8 weeks (n=3) and 11 weeks (n=3) exhibited distinct ASC, which expressed α-SMA and aberrant matrix deposition. In contrast, only 20% of 4 week old TGFβ1/MMP-9-/- mice (n=5) examined exhibited subcapsular plaques that were α-SMA positive. Both of the 8 week old TGFβ1/MMP-9-/- (n=2) mice examined exhibited plaques with aberrant matrix deposition and α-SMA reactivity but were reduced in size when compared to that of TGFβ1/MMP-9+/+ mice. Furthermore, 66% of TGFβ1/MMP-9-/- mice at 11 weeks (n= 3) exhibited ASC formation.

Conclusions: : Lack of MMP-9 in the presence of sustained lens-specific TGFβ1 does not completely bock ASC formation but does substantially delay and reduce its incidence when compared to TGFβ1/MMP-9+/+ mice at similar timepoints. Thus, MMP-9 is an important modulating factor in TGFβ-mediated ASC. In the future, determining the specific mechanism by which MMP-9 mediates this ocular fibrotic disease will assist in deriving therapeutic interventions.

Keywords: transgenics/knock-outs • growth factors/growth factor receptors • cataract 

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