Amelioration of experimental arthritis by intra-articular injection of an epidermal growth factor receptor tyrosine kinase inhibitor.

Abstract:

OBJECTIVES: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.

journal_name

Clin Exp Rheumatol

authors

Chen SY,Shiau AL,Wu CL,Wang CR

subject

Has Abstract

pub_date

2015-11-01 00:00:00

pages

839-43

issue

6

eissn

0392-856X

issn

1593-098X

pii

9118

journal_volume

33

pub_type

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