PT  - JOURNAL ARTICLE
AU  - Masako To
AU  - Catherine E. Charron
AU  - Sergei A. Kharitonov
AU  - Peter J. Barnes
AU  - Kazuhiro Ito
TI  - Elevated osteoprotegerin in COPD is potentially regulated by oxidative stress dependent glycogen synthase kinase-3β and β-catenin signalling
DP  - 2011 Sep 01
TA  - European Respiratory Journal
PG  - p4753
VI  - 38
IP  - Suppl 55
4099  - http://erj.ersjournals.com/content/38/Suppl_55/p4753.short
4100  - http://erj.ersjournals.com/content/38/Suppl_55/p4753.full
SO  - Eur Respir J2011 Sep 01; 38
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.