title: Peroxisome proliferator-activated receptor δ inhibits Porphyromonas gingivalis lipopolysaccharide-induced activation of matrix metalloproteinase-2 by downregulating NADPH oxidase 4 in human gingival fibroblasts.
abstract: We investigated the roles of peroxisome proliferator-activated receptor δ (PPARδ) in Porphyromonas gingivalis-derived lipopolysaccharide (Pg-LPS)-induced activation of matrix metalloproteinase 2 (MMP-2). In human gingival fibroblasts (HGFs), activation of PPARδ by GW501516, a specific ligand of PPARδ, inhibited Pg-LPS-induced activation of MMP-2 and generation of reactive oxygen species (ROS), which was associated with reduced expression of NADPH oxidase 4 (Nox4). These effects were significantly smaller in the presence of small interfering RNA targeting PPARδ or the specific PPARδ inhibitor GSK0660, indicating that PPARδ is involved in these events. In addition, modulation of Nox4 expression by small interfering RNA influenced the effect of PPARδ on MMP-2 activity, suggesting a mechanism in which Nox4-derived ROS modulates MMP-2 activity. Furthermore, c-Jun N-terminal kinase and p38, but not extracellular signal-regulated kinase, mediated PPARδ-dependent inhibition of MMP-2 activity in HGFs treated with Pg-LPS. Concomitantly, PPARδ-mediated inhibition of MMP-2 activity was associated with the restoration of types I and III collagen to levels approaching those in HGFs not treated with Pg-LPS. These results indicate that PPARδ-mediated downregulation of Nox4 modulates cellular redox status, which in turn plays a critical role in extracellular matrix homeostasis through ROS-dependent regulation of MMP-2 activity.
authors.affiliation: Department of Animal Biotechnology, Konkuk University, Seoul, Korea.
authors.forename: T
authors.initials: T
authors.lastname: Yoo
authors.affiliation: Department of Animal Biotechnology, Konkuk University, Seoul, Korea.
authors.forename: S A
authors.initials: SA
authors.lastname: Ham
authors.affiliation: Department of Animal Biotechnology, Konkuk University, Seoul, Korea.
authors.forename: J S
authors.initials: JS
authors.lastname: Hwang
authors.affiliation: Department of Animal Biotechnology, Konkuk University, Seoul, Korea.
authors.forename: W J
authors.initials: WJ
authors.lastname: Lee
authors.affiliation: Department of Nursing, Semyung University, Chungbuk, Korea.
authors.forename: K S
authors.initials: KS
authors.lastname: Paek
authors.affiliation: Department of Animal Biotechnology, Konkuk University, Seoul, Korea.
authors.forename: J W
authors.initials: JW
authors.lastname: Oh
authors.affiliation: Department of Animal Biotechnology, Konkuk University, Seoul, Korea.
authors.forename: J H
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Animal Biotechnology, Konkuk University, Seoul, Korea.
authors.forename: J T
authors.initials: JT
authors.lastname: Do
authors.affiliation: Department of Internal Medicine, Pusan National University School of Korean Medicine, Yangsan, Kyeongnam, Korea.
authors.forename: C W
authors.initials: CW
authors.lastname: Han
authors.affiliation: Department of Biomedical Science, CHA University, Seongnam, Gyeonggi-Do, Korea.
authors.forename: J H
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Animal Biotechnology, Konkuk University, Seoul, Korea.
authors.forename: H G
authors.initials: HG
authors.lastname: Seo
mesh_terms: D002478:Cells, Cultured; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D004789:Enzyme Activation; D005347:Fibroblasts / Q000187:drug effects / Q000382:microbiology*; D005881:Gingiva / Q000166:cytology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000378:metabolism* / Q000494:pharmacology; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000235:genetics*; D047494:PPAR delta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016966:Porphyromonas gingivalis / Q000187:drug effects / Q000378:metabolism* / Q000472:pathogenicity; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species / Q000378:metabolism; D013450:Sulfones / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: C529769:GSK0660; C425931:GW 501516; D008070:Lipopolysaccharides; D047494:PPAR delta; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D013450:Sulfones; D013844:Thiazoles; D013876:Thiophenes; D003094:Collagen; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498910:NOX4 protein, human; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020778:Matrix Metalloproteinase 2
keywords: NADPH oxidase 4; Porphyromonas gingivalis-derived lipopolysaccharide; collagen; matrix metalloproteinase-2; peroxisome proliferator-activated receptor δ; reactive oxygen species