Anti-connective tissue growth factor antibody treatment reduces Extracellular matrix production in Trabecular meshwork and Lamina Cribrosa cells

Deborah M. Wallace, Abbot F. Clark, Kenneth E. Lipson, Darrell Andrews, John K. Crean, Colm J. O'Brien

Research output: Contribution to journalArticle

38 Scopus citations

Abstract

Purpose. We have previously demonstrated elevated levels of connective tissue growth factor (CTGF/CCN2) in the aqueous humor (AqH) of pseudoexfoliation glaucoma (PXFG) patients when compared with cataract controls. Furthermore, there is a significant trabecular meshwork (TM) and lamina cribrosa (LC) fibrotic phenotype associated with glaucoma, possibly driven by CTGF. The purpose of this study was to investigate the potential of anti-CTGF immunotherapy in glaucoma. Methods. Primary TM and LC cells were cultured from human donors with (GTM/GLC) and without (NTM/NLC) primary open angle glaucoma (POAG). Aqueous humor samples from PXFG, POAG, and control cataract patients were applied to N/GTM and N/GLC cells in the presence or absence of a therapeutic, humanized monoclonal anti-CTGF antibody FG-3019 (10 lg/mL). Hydrogen peroxide (H2O2) was also used as a stimulus. Expression of fibrotic genes (fibronectin-1, fibrillin-1, CTGF, collagen type I a1, and a-smooth muscle actin) was assessed by q-PCR. Protein expression of collagen 1A1 and a-smooth muscle actin was examined in N/G TM cells by SDS-PAGE. The modulatory effect of FG-3019 (10 lg/mL) and IgG (10 lg/mL) were also assessed. Results. Treatment of cells with AqH from PXFG and POAG patients and H2O2 induced a significant (P < 0.05) increase in expression of profibrotic genes, which was significantly reduced by pretreatment with FG-3019 (P < 0.05). FG-3019 also reduced expression of a-smooth muscle actin and collagen 1A1 protein expression in N/GTM cells. Conclusions. FG-3019 is effective in blocking extracellular matrix production in TM and LC cells, thus supporting a role for the use of anti-CTGF immunotherapy in the treatment of glaucoma. 2013 The Association for Research in Vision and Ophthalmology, Inc.

Original languageEnglish
Pages (from-to)7836-7848
Number of pages13
JournalInvestigative Ophthalmology and Visual Science
Volume54
Issue number13
DOIs
StatePublished - 7 Nov 2013

Keywords

  • Extracellular matrix
  • Glaucoma pharmacology
  • Lamina cribrosa
  • Trabecular meshwork

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