| 17β-Estradiol inhibits the doxorubicin-induced apoptosis via block of volume-sensitive Cl(-) current in rabbit articular chondrocytes. | |
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MedLine Citation:
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PMID: 22142024 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Background and purpose: Chondrocyte apoptosis contributes to disruption of cartilage integrity in osteoarthritis. Recent evidence suggested that the volume-sensitive organic osmolyte/anion channel (VSOAC, I(Cl,vol) ) plays a functional role in the development of cell shrinkage associated with apoptosis (apoptotic volume decrease) in several cell types. This study aimed at investigating cellular effects of 17β-estradiol on the doxorubicin-induced apoptotic responses in rabbit articular chondrocytes. Experimental approach: Whole-cell membrane currents and cross-sectional area were measured from chondrocytes using patch-clamp method and microscopic cell imaging, respectively. Caspase-3/7 activity was assayed as an index of apoptosis. Key results: Addition of doxorubicin (1 µM) to isosmotic bath solution rapidly activated the Cl(-) current with properties similar to those of I(Cl,vol) in chondrocytes. Doxorubicin also gradually decreased the cross-sectional area of chondrocytes, followed by elevation of caspase-3/7 activity, which were both totally abolished by the I(Cl,vol) blocker 4-(2-butyl-6,7-dichloro-2-cyclopentyl-indan-1-on-5-yl) oxybutyric acid (20 µM). Pretreatment of chondrocytes with 17β-estradiol (1 nM) for short (approximately 10 min) and long (24 h) periods almost totally prevented the doxorubicin-induced activation of I(Cl,vol) and subsequent elevation of caspase-3/7 activity. These effects of 17β-estradiol were significantly attenuated by the estrogen receptor blocker ICI 182780 (10 µM) as well as the phosphatidylinositol-3-kinase (PI3K) inhibitors wortmannin (100 nM) and LY294002 (20 µM). Testosterone (10 nM) had no effect on the doxorubicin-induced Cl(-) current. Conclusions and implications: 17β-Estradiol prevents the doxorubicin-induced cell shrinkage mediated through activation of I(Cl,vol) and subsequent induction of apoptosis signals, thorough a membrane receptor-dependent PI3K pathway in rabbit articular chondrocytes. |
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Authors:
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Kousuke Kumagai; Shinji Imai; Futoshi Toyoda; Noriaki Okumura; Eiji Isoya; Hiroshi Matsuura; Yoshitaka Matsusue |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-12-5 |
Journal Detail:
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Title: British journal of pharmacology Volume: - ISSN: 1476-5381 ISO Abbreviation: - Publication Date: 2011 Dec |
Date Detail:
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Created Date: 2011-12-6 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 7502536 Medline TA: Br J Pharmacol Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
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© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society. |
Affiliation:
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Department of Orthopaedic Surgery, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan Department of Physiology, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan. |
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