4.7 Article

17ß-Oestradiol inhibits doxorubicin-induced apoptosis via block of the volume-sensitive Cl- current in rabbit articular chondrocytes

期刊

BRITISH JOURNAL OF PHARMACOLOGY
卷 166, 期 2, 页码 702-720

出版社

WILEY
DOI: 10.1111/j.1476-5381.2011.01802.x

关键词

chondrocyte; osteoarthritis; volume-sensitive Cl- current; 17 ss-oestradiol; apoptosis; caspase; doxorubicin

资金

  1. Japan Society for the Promotion of Science
  2. Grants-in-Aid for Scientific Research [23590258] Funding Source: KAKEN

向作者/读者索取更多资源

BACKGROUND AND PURPOSE Chondrocyte apoptosis contributes to disruption of cartilage integrity in osteoarthritis. Recent evidence suggested that the volume-sensitive organic osmolyte/anion channel [volume-sensitive (outwardly rectifying) Cl- current (ICl,vol)] plays a functional role in the development of cell shrinkage associated with apoptosis (apoptotic volume decrease) in several cell types. In this study, we investigated the cellular effects of 17 beta-oestradiol on doxorubicin-induced apoptotic responses in rabbit articular chondrocytes. EXPERIMENTAL APPROACH Whole-cell membrane currents and cross-sectional area were measured from chondrocytes using a 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 mM) to isosmotic bath solution rapidly activated the Cl-current with properties similar to those of ICl, vol in chondrocytes. Doxorubicin also gradually decreased the cross-sectional area of chondrocytes, followed by enhanced caspase-3/ 7 activity; both of these responses were totally abolished by the ICl, vol blocker DCPIB (20 mM). Pretreatment of chondrocytes with 17b-oestradiol (1 nM) for short (approximately 10 min) and long (24 h) periods almost completely prevented the doxorubicin-induced activation of ICl, vol and subsequent elevation of caspase-3/ 7 activity. These effects of 17b-oestradiol were significantly attenuated by the oestrogen receptor blocker ICI 182780 (10 mM), as well as the phosphatidyl inositol-3-kinase (PI3K) inhibitors wortmannin (100 nM) and LY294002 (20 mM). Testosterone (10 nM) had no effect on the doxorubicin-induced Cl-current. CONCLUSIONS AND IMPLICATIONS 17b-Oestradiol prevents the doxorubicin-induced cell shrinkage mediated through activation of ICl, vol and subsequent induction of apoptosis signals, through a membrane receptor-dependent PI3K pathway in rabbit articular chondrocytes.

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