Expression of HIF prolyl hydroxylase isozymes in growth plate chondrocytes: Relationship between maturation and apoptotic sensitivity

The overall goal of the current study was to examine the functional activity of the prolyl hydroxylases (PHDs) in maturing chondrocytes. Herein, we show for the first time that the PHDs are expressed in the maturing zone of the growth plate, and by a chondrocytic cell line. We determined if this pro...

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Bibliographic Details
Published in:	Journal of cellular physiology Vol. 210; no. 1; pp. 257 - 265
Main Authors:	Terkhorn, S.P., Bohensky, J., Shapiro, I.M., Koyama, E., Srinivas, V.
Format:	Journal Article
Language:	English
Published:	Hoboken Wiley Subscription Services, Inc., A Wiley Company 01-01-2007
Subjects:	Amino Acids, Dicarboxylic - pharmacology Animals Apoptosis - drug effects Apoptosis Regulatory Proteins - metabolism Bone Morphogenetic Proteins - pharmacology Caspase 3 - metabolism Cell Differentiation - drug effects Cell Line Cell Proliferation - drug effects Cell Survival - drug effects Chondrocytes - cytology Chondrocytes - drug effects Chondrocytes - enzymology Dose-Response Relationship, Drug Enzyme Activation - drug effects Enzyme Inhibitors - pharmacology Growth Plate - cytology Growth Plate - drug effects Growth Plate - embryology Growth Plate - enzymology Humans Hydrogen Peroxide - pharmacology Hypoxia-Inducible Factor 1, alpha Subunit - genetics Hypoxia-Inducible Factor 1, alpha Subunit - metabolism Isoenzymes - metabolism Mice Oxidoreductases - metabolism Procollagen-Proline Dioxygenase - antagonists & inhibitors Procollagen-Proline Dioxygenase - metabolism RNA, Small Interfering - genetics RNA, Small Interfering - metabolism Time Factors Transfection
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Summary:	The overall goal of the current study was to examine the functional activity of the prolyl hydroxylases (PHDs) in maturing chondrocytes. Herein, we show for the first time that the PHDs are expressed in the maturing zone of the growth plate, and by a chondrocytic cell line. We determined if this protein and its substrate, hypoxia inducible factor (HIF)‐1α, modulated the induction of apoptosis. Using a chondrocyte cell line that matured in culture, we inhibited HIF‐1α expression using siRNA technology and pharmacologically blocked PHD activity. We noted that PHD suppression sensitized the cells to an apoptotic challenge with H2O2. We next examined the interplay between the PHDs and HIF‐1α by suppressing HIF‐1α and blocking PHD activity. We noted reduced killing when the mature HIF‐silenced cells were challenged with H2O2. In contrast, there was limited change in the viability of immature cells. Based on these differences in chondrocyte susceptibility, it is concluded that HIF‐1α sensitizes maturing cells to H2O2‐mediated killing. We next determined if this change in the viability of the PHD‐inhibited cells was linked to changes in activation of caspase‐3. It was noted that there was a minimal change in enzyme activity of the PHD‐inhibited HIF‐1α suppressed cells. Finally, we found that as the chondrocytes mature, the activities of catalase and SOD were significantly reduced and that there was a decrease in the levels of Bcl‐2 and BclXL. This loss of protective activity together with the changes mediated by HIF would be expected to generate conditions that would favor the induction of chondrocyte apoptosis. J. Cell. Physiol. 210: 257–265, 2007. © 2006 Wiley‐Liss, Inc.
Bibliography:	ark:/67375/WNG-6LJWQ3F7-5 ArticleID:JCP20873 National Institutes of Health - No. DE13319; No. DE10875; No. DE15694; No. DE16383; No. DE15753 istex:E5B65F27A487F88DD4CF9F3700DB400657A2FCE8 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0021-9541 1097-4652
DOI:	10.1002/jcp.20873