RT Journal Article
SR Electronic
T1 Elevated osteoprotegerin in COPD is potentially regulated by oxidative stress dependent glycogen synthase kinase-3β and β-catenin signalling
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP p4753
VO 38
IS Suppl 55
A1 Masako To
A1 Catherine E. Charron
A1 Sergei A. Kharitonov
A1 Peter J. Barnes
A1 Kazuhiro Ito
YR 2011
UL http://erj.ersjournals.com/content/38/Suppl_55/p4753.abstract
AB We recently reported that sputum osteoprotegerin (OPG) in COPD is higher than that in controls and is a potential biomarker in COPD (To M et.al. CHEST 2010 Dec 2 [Epub ahead of print]). However, the molecular mechanism involved in OPG elevation in COPD was not clarified yet. Here we investigated the role of glycogen synthase kinase-3β (GSK-3β) and β-catenin in OPG transcription, especially under oxidative stress.A549 cells, an alveolar epithelial cell line, were treated with cigarette smoke conditioned media (CSM), and β-catenin protein was determined by westernblot. CSM induced OPG release (measured by ELISA) with a maximum induction of 147% and also increased β-catenin protein expression in a concentration-dependent manner with a maximum induction of 161%. A549 cells were transfected with β-catenin siRNA using lipofectamine for specific knockdown (KD) of β-catenin, and IL-1β stimulated OPG production by the A549 cells was measured by ELISA. β-catenin KD showed significantly lower OPG production at baseline and after IL-1β stimulation compared to non- transfected controls (466±13 pg/ml in β-catenin KD and 1712±35pg/ml in wild type without IL-1β, and 1213±37 pg/ml in β-catenin KD and 2669±16pg/ml in wild type under IL-1β stimulation). The inhibitor of GSK-3β, which controls β-catenin stabilisation, significantly increased OPG production with a maximum induction of 161% and with EC50 of 1.2 mM.Thus, defect of GSK-3β causes β-catenin expression, leading upregulation of OPG. This will be a new insight on molecular mechanism of COPD pathogenesis.