Foiling Fibrosis

Sci. Signal.  17 Dec 2013:
Vol. 6, Issue 306, pp. ec306
DOI: 10.1126/scisignal.2005003

Excessive deposition of collagenous extracellular matrix by myofibroblasts in a process called fibrosis can disrupt organ function. Transforming growth factor–β1 (TGF-β1) is a cytokine that promotes fibrosis, and the latent form of TGF-β1 can be activated by integrins, transmembrane receptors for extracellular matrix proteins, on the surface of myofibroblasts. Hepatic stellate cells are thought to give rise to fibroblasts in the liver, and Henderson et al. (see also Hinz) found that genes could be deleted in hepatic stellate cells using Cre recombinase under the control of the promoter for Pdgfrb (which encodes platelet-derived growth factor receptor β). Itgavflox/flox;Pdgfrb-Cre mice were deficient for αv integrin in hepatic stellate cells (Itgav encodes αv integrin) and were protected from chemically induced liver fibrosis. When activated in culture, hepatic stellate cells lacking αv integrin exhibited decreased expression of genes encoding extracellular matrix proteins (an effect that was similar to that produced by application of an αv integrin-blocking antibody to wild-type cells), decreased secretion of TGF-β1, and decreased activation of a TGF-β1 effector (the transcription factor Smad4) compared with control cells. Itgavflox/flox;Pdgfrb-Cre mice were also deficient in αv integrin in myofibroblasts in the lung and kidney and were protected against chemically induced lung fibrosis and surgically induced kidney fibrosis. CWHM 12, but not its R enantiomer CWHM 96, blocked ligand binding to αv integrin in vitro. Administration of CWHM 12, but not CWHM 96, diminished liver fibrosis when administered to wild-type mice before the induction of fibrosis and also reduced the progression of liver and lung fibrosis when administered to mice after the development of fibrosis. Thus, small-molecule inhibitors of αv integrin could be developed to prevent or inhibit the progression of fibrosis.

N. C. Henderson, T. D. Arnold, Y. Katamura, M. M. Giacomini, J. D. Rodriguez, J. H. McCarty, A. Pellicoro, E. Raschperger, C. Betsholtz, P. G. Ruminski, D. W. Griggs, M. J. Prinsen, J. J. Maher, J. P. Iredale, A. Lacy-Hulbert, R. H. Adams, D. Sheppard, Targeting of αv integrin identifies a core molecular pathway that regulates fibrosis in several organs. Nat. Med. 19, 1617–1624 (2013). [PubMed]

B. Hinz, It has to be the αv: Myofibroblast integrins activate latent TGF-β1. Nat. Med. 19, 1567–1568 (2013). [PubMed]