November 3, 2007
American Society of Nephrology (ASN) Renal Week 2007, San Francisco, CA
Abstract SA-PO325

FG-3019 modulates CTGF-mediated mesangial cell adhesion and cytoskeletal signaling: implications for anti-CTGF directed therapeutic intervention. Gaffney, A.¹, Oliver, N.², Godson, C.¹ and Crean, JK.³

1 Diabetes Research Centre, UCD School of Biomolecular and Biomedical Science and UCD School of Medicine and Medical Science, 3 Conway Institute, University College Dublin, Belfield, Dublin 4. 2 Fibrogen Inc, Gateway Boulevard, South San Francisco, CA 94080 USA.

Abstract: Elevated expression of glomerular Connective Tissue Growth Factor (CTGF) plays an important role in the development and progression of Diabetic Nephrology, at least in part through increasing dysregulation of mesangial cell extracellular matrix production and actin cytoskeletal remodelling resulting in altered contractility. While no specific signalling receptor has been identified for CTGF, it can bind to integrins, initiating src-dependant cascades including FAK/paxillin and MAP Kinase (MAPK) pathways. Here we describe the modulation of CTGF-dependent cell adhesion and adhesive responses by the fully human CTGF-specific monoclonal antibody, FG-3019. We investigated the in-vitro effects of recombinant human CTGF (rhCTGF) on cell adhesion dynamics and the activation status of components of the p42/44 MAPK, p38 MAPK and FAK pathways and examined the effects of FG-3019 on these two CTGF-mediated responses. Adhesion of mesangial cells to rhCTGF stimulated p38 MAPK, p42/44 MAPK and Paxillin phosphorylation within 30 minutes. When plates were precoated with FG-3019, there was an abrogation of the p38 MAPK and paxillin phosphorylation responses. However, no such changes were observed with respect to the p42/44 MAPK phosphorylation. The ability of rhCTGF to promote cell adhesion was also diminished by FG-3019. Immunofluorescent microscopy revealed that rhCTGF stimulated focal adhesion formation upon adhesion, as evidenced by increased staining for vinculin. Again, this response was attenuated when slides were pretreated with FG-3019. In conclusion, the ability of FG-3019 to abrogate the effects of CTGF-mediated mesangial cell adhesion and cytoskeletal signalling suggests it could represent a future anti-CTGF directed therapeutic intervention and provides further mechanistic insight into CTGF signalling.

See also November 7, 2007 press release