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Stefanie Berger, Anima Buehler, Fee Werner, Gottfried Martin, Hong Han, Daniel Boehringer, Gunther Schlunck, Hansjürgen Agostini, Thomas Reinheckel, Andreas Stahl; Loss of Cathepsin B and Z reduces matrix invadosome formation, endothelial sprouting and CNV area in mice. Invest. Ophthalmol. Vis. Sci. 2013;54(15):326. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Cathepsin B and Z are recently identified members of the papain-like cysteine protease family. They are expressed by many cell types and involved in protein turnover and matrix invasion. Ctsb is a known modulator of tumor angiogenesis. We therefore investigated the angiomodulatory function of these cathepsins in vitro as well as in a mouse model of laser-induced choroidal neovascularization (Laser-CNV).
Ctsb-/- mice, Ctsz-/- mice and Ctsb/Ctsz double knockouts (Ctsb/z DKO) were generated on a C57BL/6 background. Knockout and C57BL/6 wild type (WT) controls underwent retinal argon laser coagulation to induce choroidal neovascularization (CNV). 14 days after laser treatment the CNV area was quantified individually for each lesion. In vitro analysis was performed using cathepsin inhibitors in endothelial cell (EC) spheroid sprouting and invadosome assays.
Cathepsin single or double knockout animals do not show gross morphological abnormalities on light microscopy level. In the Laser CNV model, however, Ctsb/z DKO mice display a significantly reduced CNV area compared to WT (p=0.012) while single knockouts do not differ significantly from WT. In line with these findings, VEGF-induced EC spheroid sprouting and invadosome assays were not significantly altered by a specific cathepsin B inhibitor alone, but significantly suppressed when more than one cathepsins were inhibited.
Our results demonstrate that the knockout of either Ctsb or Ctsz alone does not significantly modulate experimental choroidal angiogenesis, EC speroid sprouting or invadosome formation. However, Laser-CNV formation is significantly reduced in Ctsb/z DKO mice and EC sprouting and invadosome formation are reduced when more than one cathepin is inhibited. These results suggest an angiomodulatory potential of cathepsins with partial functional redundancies and compensation between different cathepsin family members.
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