Article (Scientific journals)
Heme Oxygenase-1 Regulates Matrix Metalloproteinase MMP-1 Secretion and Chondrocyte Cell Death via Nox4 NADPH Oxidase Activity in Chondrocytes
Rousset, Francis; NGUYEN, Minh Vu Chong; Grange, Laurent et al.
2013In PLoS ONE, 8 (6)
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Keywords :
DNA fragmentation; Apoptosis; Carbon Monoxide; Chondrocytes; Green Fluorescent Proteins; HEK293 Cells; Heme; Heme Oxygenase-1; Humans; Interleukin-1beta; Matrix Metalloproteinase 1; NADPH Oxidase; Osteoarthritis; Protein Multimerization; Protein Transport; Recombinant Fusion Proteins
Abstract :
[en] Interleukin-1β (IL-1β) activates the production of reactive oxygen species (ROS) and secretion of MMPs as well as chondrocyte apoptosis. Those events lead to matrix breakdown and are key features of osteoarthritis (OA). We confirmed that in human C-20/A4 chondrocytes the NADPH oxidase Nox4 is the main source of ROS upon IL-1β stimulation. Since heme molecules are essential for the NADPH oxidase maturation and activity, we therefore investigated the consequences of the modulation of Heme oxygenase-1 (HO-1), the limiting enzyme in heme catabolism, on the IL-1β signaling pathway and more specifically on Nox4 activity. Induction of HO-1 expression decreased dramatically Nox4 activity in C-20/A4 and HEK293 T-REx™ Nox4 cell lines. Unexpectedly, this decrease was not accompanied by any change in the expression, the subcellular localization or the maturation of Nox4. In fact, the inhibition of the heme synthesis by succinylacetone rather than heme catabolism by HO-1, led to a confinement of the Nox4/p22phox heterodimer in the endoplasmic reticulum with an absence of redox differential spectrum highlighting an incomplete maturation. Therefore, the downregulation of Nox4 activity by HO-1 induction appeared to be mediated by carbon monoxide (CO) generated from the heme degradation process. Interestingly, either HO-1 or CO caused a significant decrease in the expression of MMP-1 and DNA fragmentation of chondrocytes stimulated by IL-1β. These results all together suggest that a modulation of Nox4 activity via heme oxygenase-1 may represent a promising therapeutic tool in osteoarthritis. © 2013 Rousset et al.
Disciplines :
Biochemistry, biophysics & molecular biology
Identifiers :
eid=2-s2.0-84879260319
Author, co-author :
Rousset, Francis;  Université Joseph Fourier, AGIM GREPI FRE CNRS 3405, Grenoble, France
NGUYEN, Minh Vu Chong ;  University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit
Grange, Laurent;  Université Joseph Fourier, AGIM GREPI FRE CNRS 3405, Grenoble, France, Rheumatology Department, Grenoble Teaching Hospital, CHU Hôpital Sud, Grenoble, France
Morel, Françoise;  Université Joseph Fourier, AGIM GREPI FRE CNRS 3405, Grenoble, France
Lardy, Bernard;  Université Joseph Fourier, AGIM GREPI FRE CNRS 3405, Grenoble, France, Laboratoire de Biochimie Enzyme et Protéine-DBTP, Institut de Biologie et de Pathologie, Centre Hospitalier Universitaire (CHU), Grenoble, France
External co-authors :
yes
Language :
English
Title :
Heme Oxygenase-1 Regulates Matrix Metalloproteinase MMP-1 Secretion and Chondrocyte Cell Death via Nox4 NADPH Oxidase Activity in Chondrocytes
Publication date :
2013
Journal title :
PLoS ONE
ISSN :
1932-6203
Publisher :
Public Library of Science, United States - California
Volume :
8
Issue :
6
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBilu :
since 16 May 2016

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