title: Peroxisome proliferator-activated receptor-gamma-independent repression of collagenase gene expression by 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid and prostaglandin 15-deoxy-delta(12,14) J2: a role for Smad signaling.
abstract: Matrix metalloproteinases (MMPs) degrade extracellular matrix components, and overexpression of these enzymes contributes to tissue destruction in arthritis. Of particular importance are the collagenases, MMP-1 and MMP-13, which have high activity against the interstitial collagens in cartilage. In this study, we address the mechanisms of two inhibitors of collagenase gene expression, the synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) and 15-deoxy-delta(12,14)-prostaglandin J2 (15-dPGJ2). Although both inhibitors are ligands for the nuclear hormone receptor peroxisome proliferator-activated receptor-gamma (PPAR-gamma), a connection between PPAR-gamma and collagenase gene expression has yet to be established. Here, we test the hypothesis that CDDO and 15-dPGJ2 use PPAR-gamma to repress MMP gene expression. Our findings with the PPAR-gamma antagonist 2-[4-[2-[3-(2,4-difluorophenyl)-1-heptylureido]ethyl]rsqb]-phenylsulfanyl]-2-methylpropionic acid (GW9662) and mouse embryonic fibroblasts lacking PPAR-gamma demonstrate that CDDO and 15-dPGJ2 use PPAR-gamma-independent mechanisms to inhibit collagenase gene expression. To address a potential PPAR-gamma-independent mechanism leading to the repression of MMPs by CDDO, we tested the effect of CDDO on the transforming growth factor-beta (TGF-beta) signaling pathway. We found that CDDO requires Smads (transcription factors activated by TGF-beta) for the repression of MMP-1. Specifically, MMP-1 is inhibited neither by CDDO in the absence of TGF-beta receptor-activated Smad3 nor when a negative regulator, Smad7, attenuates TGF-beta signaling. We conclude that CDDO represses MMP gene expression through a novel PPAR-gamma-independent mechanism that requires Smad signaling.
authors.affiliation: Department of Biochemistry, Dartmouth Medical School, Hanover, New Hampshire 03756, USA.
authors.forename: Kimberlee S
authors.initials: KS
authors.lastname: Mix
authors.forename: Charles I
authors.initials: CI
authors.lastname: Coon
authors.forename: Evan D
authors.initials: ED
authors.lastname: Rosen
authors.forename: Nanjoo
authors.initials: N
authors.lastname: Suh
authors.forename: Michael B
authors.initials: MB
authors.lastname: Sporn
authors.forename: Constance E
authors.initials: CE
authors.lastname: Brinckerhoff
mesh_terms: D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D017364:Collagenases / Q000096:biosynthesis / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004794:Enzyme Repression / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology; D006801:Humans; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D051785:Smad Proteins; D015534:Trans-Activators / Q000502:physiology*; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*
chemical_list: C097240:15-deoxy-delta(12,14)-prostaglandin J2; C116817:2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid; D004268:DNA-Binding Proteins; D061965:Matrix Metalloproteinase Inhibitors; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D051785:Smad Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D009828:Oleanolic Acid; D017364:Collagenases; D015230:Prostaglandin D2