title: Heme oxygenase-1 regulates matrix metalloproteinase MMP-1 secretion and chondrocyte cell death via Nox4 NADPH oxidase activity in chondrocytes.
abstract: 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/p22(phox) 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.
authors.affiliation: Université Joseph Fourier, AGIM GREPI FRE CNRS 3405, Grenoble, France. francisrousset@yahoo.fr
authors.forename: Francis
authors.initials: F
authors.lastname: Rousset
authors.forename: Minh Vu Chuong
authors.initials: MV
authors.lastname: Nguyen
authors.forename: Laurent
authors.initials: L
authors.lastname: Grange
authors.forename: Françoise
authors.initials: F
authors.lastname: Morel
authors.forename: Bernard
authors.initials: B
authors.lastname: Lardy
mesh_terms: D017209:Apoptosis; D002248:Carbon Monoxide / Q000494:pharmacology; D019902:Chondrocytes / Q000201:enzymology* / Q000502:physiology; D053938:DNA Fragmentation; D049452:Green Fluorescent Proteins / Q000378:metabolism; D057809:HEK293 Cells; D006418:Heme / Q000096:biosynthesis; D051547:Heme Oxygenase-1 / Q000502:physiology*; D006801:Humans; D053583:Interleukin-1beta / Q000502:physiology; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism*; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010003:Osteoarthritis / Q000201:enzymology; D055503:Protein Multimerization; D021381:Protein Transport; D011993:Recombinant Fusion Proteins / Q000378:metabolism
chemical_list: D053583:Interleukin-1beta; D011993:Recombinant Fusion Proteins; D049452:Green Fluorescent Proteins; D006418:Heme; D002248:Carbon Monoxide; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498910:NOX4 protein, human; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1