Targeting of αv integrin identifies a core molecular pathway that regulates fibrosis in several organs.

Abstract

Myofibroblasts are the major source of extracellular matrix components that accumulate during tissue fibrosis, and hepatic stellate cells (HSCs) are believed to be the major source of myofibroblasts in the liver. To date, robust systems to genetically manipulate these cells have not been developed. We report that Cre under control of the promoter of Pdgfrb (Pdgfrb-Cre) inactivates loxP-flanked genes in mouse HSCs with high efficiency. We used this system to delete the gene encoding α(v) integrin subunit because various α(v)-containing integrins have been suggested as central mediators of fibrosis in multiple organs. Such depletion protected mice from carbon tetrachloride-induced hepatic fibrosis, whereas global loss of β₃, β₅ or β₆ integrins or conditional loss of β₈ integrins in HSCs did not. We also found that Pdgfrb-Cre effectively targeted myofibroblasts in multiple organs, and depletion of the α(v) integrin subunit using this system was protective in other models of organ fibrosis, including pulmonary and renal fibrosis. Pharmacological blockade of α(v)-containing integrins by a small molecule (CWHM 12) attenuated both liver and lung fibrosis, including in a therapeutic manner. These data identify a core pathway that regulates fibrosis and suggest that pharmacological targeting of all α(v) integrins may have clinical utility in the treatment of patients with a broad range of fibrotic diseases.

• Authors: Neil C Henderson, Thomas D Arnold, Yoshio Katamura, Marilyn M Giacomini, Juan D Rodriguez, Joseph H McCarty, Antonella Pellicoro, Elisabeth Raschperger, Christer Betsholtz, Peter G Ruminski, David W Griggs, Michael J Prinsen, Jacquelyn J Maher, John P Iredale, Adam Lacy-Hulbert, Ralf H Adams, Dean Sheppard
• Journal: Nature medicine (Nat Med) Vol. 19 Issue 12 Pg. 1617-24 (Dec 2013) ISSN: 1546-170X [Electronic] United States
• PMID: 24216753 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Integrin alphaV

Topics

• Animals
• Cells, Cultured
• Drug Evaluation, Preclinical
• Female
• Fibrosis (genetics)
• Gene Targeting
• Integrin alphaV (genetics, metabolism)
• Kidney (metabolism, pathology)
• Kidney Diseases (genetics, pathology)
• Liver Cirrhosis (genetics, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Myofibroblasts (metabolism, pathology)
• Pulmonary Fibrosis (genetics, pathology)
• Signal Transduction (physiology)