Targeting of αv integrin identifies a core molecular pathway that regulates fibrosis in several organs.
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.
1] Lung Biology Center, Department of Medicine, University of California, San Francisco, San Francisco, California, USA. [2] Medical Research Council Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
Neil C
NC
Henderson
Thomas D
TD
Arnold
Yoshio
Y
Katamura
Marilyn M
MM
Giacomini
Juan D
JD
Rodriguez
Joseph H
JH
McCarty
Antonella
A
Pellicoro
Elisabeth
E
Raschperger
Christer
C
Betsholtz
Peter G
PG
Ruminski
David W
DW
Griggs
Michael J
MJ
Prinsen
Jacquelyn J
JJ
Maher
John P
JP
Iredale
Adam
A
Lacy-Hulbert
Ralf H
RH
Adams
Dean
D
Sheppard
D000818:Animals; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D005260:Female; D005355:Fibrosis / Q000235:genetics; D018390:Gene Targeting; D039564:Integrin alphaV / Q000235:genetics / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism / Q000473:pathology*; D007674:Kidney Diseases / Q000235:genetics* / Q000473:pathology; D008103:Liver Cirrhosis / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058628:Myofibroblasts / Q000378:metabolism / Q000473:pathology; D011658:Pulmonary Fibrosis / Q000235:genetics* / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology
D039564:Integrin alphaV