title: Inhibition of epidermal growth factor receptor tyrosine kinase ameliorates collagen-induced arthritis.
abstract: Rheumatoid arthritis (RA) is an autoimmune synovitis characterized by the formation of pannus and the destruction of cartilage and bone in the synovial joints. Although immune cells, which infiltrate the pannus and promote inflammation, play a prominent role in the pathogenesis of RA, other cell types also contribute. Proliferation of synovial fibroblasts, for example, underlies the formation of the pannus, while proliferation of endothelial cells results in neovascularization, which supports the growth of the pannus by supplying it with nutrients and oxygen. The synovial fibroblasts also promote inflammation in the synovium by producing cytokines and chemokines. Finally, osteoclasts cause the destruction of bone. In this study, we show that erlotinib, an inhibitor of the tyrosine kinase epidermal growth factor receptor (EGFR), reduces the severity of established collagen-induced arthritis, a mouse model of RA, and that it does so by targeting synovial fibroblasts, endothelial cells, and osteoclasts. Erlotinib-induced attenuation of autoimmune arthritis was associated with a reduction in number of osteoclasts and blood vessels, and erlotinib inhibited the formation of murine osteoclasts and the proliferation of human endothelial cells in vitro. Erlotinib also inhibited the proliferation and cytokine production of human synovial fibroblasts in vitro. Moreover, EGFR was highly expressed and activated in the synovium of mice with collagen-induced arthritis and patients with RA. Taken together, these findings suggest that EGFR plays a central role in the pathogenesis of RA and that EGFR inhibition may provide benefits in the treatment of RA.
authors.affiliation: Division of Immunology and Rheumatology, Department of Medicine, Stanford University, Stanford, CA 94305, USA. christina.d.swanson@gmail.com
authors.forename: Christina D
authors.initials: CD
authors.lastname: Swanson
authors.forename: Elliot H
authors.initials: EH
authors.lastname: Akama-Garren
authors.forename: Emily A
authors.initials: EA
authors.lastname: Stein
authors.forename: Jacob D
authors.initials: JD
authors.lastname: Petralia
authors.forename: Pedro J
authors.initials: PJ
authors.lastname: Ruiz
authors.forename: Abdolhossein
authors.initials: A
authors.lastname: Edalati
authors.forename: Tamsin M
authors.initials: TM
authors.lastname: Lindstrom
authors.forename: William H
authors.initials: WH
authors.lastname: Robinson
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000201:enzymology; D001172:Arthritis, Rheumatoid / Q000201:enzymology*; D000077214:Becaplermin; D002455:Cell Division / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000235:genetics; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004353:Drug Evaluation, Preclinical; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D000069347:Erlotinib Hydrochloride; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D005786:Gene Expression Regulation / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000201:enzymology; D010010:Osteoclasts / Q000187:drug effects / Q000201:enzymology; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D020574:Proto-Oncogene Proteins c-sis / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use*; D013583:Synovial Membrane / Q000201:enzymology / Q000473:pathology
chemical_list: D016207:Cytokines; D047428:Protein Kinase Inhibitors; D020574:Proto-Oncogene Proteins c-sis; D011799:Quinazolines; D000077214:Becaplermin; D000069347:Erlotinib Hydrochloride; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; C512478:EGFR protein, human; C541485:EGFR protein, mouse; D066246:ErbB Receptors; C088860:4-((3-bromophenyl)amino)-6,7-dimethoxyquinazoline