title: Lysine-specific demethylase 1-mediated demethylation of histone H3 lysine 9 contributes to interleukin 1β-induced microsomal prostaglandin E synthase 1 expression in human osteoarthritic chondrocytes.
abstract: BACKGROUND
  Microsomal prostaglandin E synthase 1 (mPGES-1) catalyzes the terminal step in the biosynthesis of PGE2, a critical mediator in the pathophysiology of osteoarthritis (OA). Histone methylation plays an important role in epigenetic gene regulation. In this study, we investigated the roles of histone H3 lysine 9 (H3K9) methylation in interleukin 1β (IL-1β)-induced mPGES-1 expression in human chondrocytes.
  
  
  METHODS
  Chondrocytes were stimulated with IL-1β, and the expression of mPGES-1 mRNA was evaluated using real-time RT-PCR. H3K9 methylation and the recruitment of the histone demethylase lysine-specific demethylase 1 (LSD1) to the mPGES-1 promoter were evaluated using chromatin immunoprecipitation assays. The role of LSD1 was further evaluated using the pharmacological inhibitors tranylcypromine and pargyline and small interfering RNA (siRNA)-mediated gene silencing. The LSD1 level in cartilage was determined by RT-PCR and immunohistochemistry.
  
  
  RESULTS
  The induction of mPGES-1 expression by IL-1β correlated with decreased levels of mono- and dimethylated H3K9 at the mPGES-1 promoter. These changes were concomitant with the recruitment of the histone demethylase LSD1. Treatment with tranylcypromine and pargyline, which are potent inhibitors of LSD1, prevented IL-1β-induced H3K9 demethylation at the mPGES-1 promoter and expression of mPGES-1. Consistently, LSD1 gene silencing with siRNA prevented IL-1β-induced H3K9 demethylation and mPGES-1 expression, suggesting that LSD1 mediates IL-1β-induced mPGES-1 expression via H3K9 demethylation. We show that the level of LSD1 was elevated in OA compared to normal cartilage.
  
  
  CONCLUSIONS
  These results indicate that H3K9 demethylation by LSD1 contributes to IL-1β-induced mPGES-1 expression and suggest that this pathway could be a potential target for pharmacological intervention in the treatment of OA and possibly other arthritic conditions.
authors.forename: Fatima Ezzahra
authors.initials: FE
authors.lastname: El Mansouri
authors.forename: Salwa-Sarah
authors.initials: SS
authors.lastname: Nebbaki
authors.forename: Mohit
authors.initials: M
authors.lastname: Kapoor
authors.forename: Hassan
authors.initials: H
authors.lastname: Afif
authors.forename: Johanne
authors.initials: J
authors.lastname: Martel-Pelletier
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Pelletier
authors.forename: Mohamed
authors.initials: M
authors.lastname: Benderdour
authors.forename: Hassan
authors.initials: H
authors.lastname: Fahmi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015153:Blotting, Western; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects* / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D056466:Histone Demethylases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology*; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism*; D008745:Methylation / Q000187:drug effects; D008875:Middle Aged; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D010003:Osteoarthritis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010293:Pargyline / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics; D000071876:Prostaglandin-E Synthases; D011485:Protein Binding; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014191:Tranylcypromine / Q000494:pharmacology
chemical_list: D006657:Histones; D053583:Interleukin-1beta; D008996:Monoamine Oxidase Inhibitors; D014191:Tranylcypromine; D010293:Pargyline; D056466:Histone Demethylases; C495195:KDM1A protein, human; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases; D008239:Lysine