Journal Reference
J Pharm Pharmacol. 2015;67(8):1075-82.
Yoshioka R1, Kita Y1, Nagahira A2, Manno A1, Makita N1, Tomita U1, Murakawa M1.
Show Affiliations- Faculty of Exploratory Pharmacology, Asubio Pharma Co., Ltd., Kobe, Japan.
- Faculty of Drug Discovery Technology, Asubio Pharma Co., Ltd., Kobe, Japan.
Abstract
OBJECTIVES:
Cadherin-11 (CDH11) is an adhesion molecule that anchors β-catenin and is involved with various functions of synovial fibroblast cells (SFCs) during the development of rheumatoid arthritis (RA). However, the mechanism of Cadherin-11 during RA-SFC proliferation is unclear. The aim of our study was to clarify the involvement of Cadherin-11 and β-catenin signalling during proliferation.
METHODS:
IL-1β-induced and tumour necrosis factor-α (TNF-α)-induced cell proliferation, with Cadherin-11 siRNAs, β-catenin-specific siRNAs and a Cadherin-11-neutralizing antibody, were assessed by 5-Bromo-2′-deoxy-uridine ELISA.
KEY FINDINGS:
Using Cadherin-11 siRNAs, there were a 42% reduction in IL-1β-induced proliferation and a 64% reduction in β-catenin protein. When β-catenin siRNAs were applied, there was a 63% reduction in IL-1β-induced proliferation. The median effective concentration (EC50 ) values for IL-1β-induced proliferation via CDH11-mediated β-catenin-dependent, total β-catenin-dependent and β-catenin-independent signalling were 0.0015, 0.016 and 0.18 ng/ml, respectively. Blocking CDH11 ligation with a CDH11-neutralizing antibody did not decrease IL-1β-induced proliferation.
CONCLUSIONS:
CDH11-mediated β-catenin signalling was 42% involved in IL-1β-induced proliferation and had the highest susceptibility to IL-1β among the proliferative signallings analysed in this study. The mode of action for Cadherin-11 during the cell proliferation was likely associated with a pool of β-catenin protein. In contrast, Cadherin-11 and β-catenin were not involved in TNF-α-induced RA-SFC proliferation.
© 2015 Royal Pharmaceutical Society.
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