title: Amelioration of experimental arthritis by intra-articular injection of an epidermal growth factor receptor tyrosine kinase inhibitor.
abstract: OBJECTIVE
  Selectively targeting signalling pathways represents a promising pharmacological approach in rheumatoid arthritis (RA). Abundant levels of epidermal growth factor receptor (EGFR) are expressed in the synovial lining layers, and the anti-arthritis effect of erlotinib and lapatinib, small-molecule EGFR tyrosine kinase inhibitors (TKIs), has been demonstrated through the systemic administration on experimental arthritis models. Nevertheless, their therapeutic responses by the intra-articular (i.a.) route remain to be explored in rheumatoid joint.
  
  
  METHODS
  The administration of an EGFR TKI (a gefitinib analogue) was explored in two in vivo models of collagen-induced arthritis (CIA) and in vitro experiments by using synovial fibroblasts (SF) from RA patients and CIA rats.
  
  
  RESULTS
  There was a significant reduction of arthritis scores in CIA mice receiving the daily intraperitoneal injection. After the onset of arthritis in CIA rats, ankle joints receiving a single i.a. injection had significant lower articular indexes with reduced synovial inflammation, pannus formation and erosion on cartilage and bone as well as total histological scores by histopathological analyses. In CIASF or RASF, upon in vitro human EGF stimulation, there was a dose-dependent increase in cell proliferation and Akt activation with suppressed responses under the EGFR TKI treatment.
  
  
  CONCLUSIONS
  These findings demonstrate the effect of i.a. injection of an EGFR TKI on amelioration of rheumatoid joint through the suppression of synovial inflammation, pannus formation and erosion on cartilage and bone in experimental arthritis, implicating targeting the i.a. EGFR signalling transduction as a pharmacological strategy.
authors: Department of Internal Medicine, National Cheng Kung University Medical College, Tainan, Taiwan.
authors: S-Y
authors: SY
authors: Chen
authors: Department of Microbiology and Immunology, National Cheng Kung University Medical College, Tainan, Taiwan.
authors: A-L
authors: AL
authors: Shiau
authors: Department of Biochemistry and Molecular Biology, National Cheng Kung University Medical College, Tainan, Taiwan.
authors: C-L
authors: CL
authors: Wu
authors: Department of Internal Medicine, National Cheng Kung University Medical College, Tainan, Taiwan.
authors: C-R
authors: CR
authors: Wang
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D018929:Cell Culture Techniques; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D000077156:Gefitinib; D006801:Humans; D007270:Injections, Intra-Articular; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology*; D051381:Rats; D013583:Synovial Membrane / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D066246:ErbB Receptors; D000077156:Gefitinib