title: Glucocorticoid-induced leucine zipper (GILZ) is involved in glucocorticoid-induced and mineralocorticoid-induced leptin production by osteoarthritis synovial fibroblasts.
abstract: Glucocorticoid-induced leucine zipper (GILZ) is a mediator of the anti-inflammatory activities of glucocorticoids. However, GILZ deletion does not impair the anti-inflammatory activities of exogenous glucocorticoids in mice arthritis models and GILZ could also mediate some glucocorticoid-related adverse events. Osteoarthritis (OA) is a metabolic disorder that is partly attributed to adipokines such as leptin, and we previously observed that glucocorticoids induced leptin secretion in OA synovial fibroblasts. The purpose of this study was to position GILZ in OA through its involvement in the anti-inflammatory activities of glucocorticoids and/or in the metabolic pathway of leptin induction. The influences of mineralocorticoids on GILZ and leptin expression were also investigated.
  
  
  
  Human synovial fibroblasts were isolated from OA patients during knee replacement surgery. Then, the cells were treated with a glucocorticoid (prednisolone), a mineralocorticoid (aldosterone), a glucocorticoid receptor (GR) antagonist (mifepristone), a selective glucocorticoid receptor agonist (Compound A), mineralocorticoid receptor (MR) antagonists (eplerenone and spironolactone), TNF-α or transforming growth factor (TGF)-β. Cells were transfected with shRNA lentiviruses for the silencing of GILZ and GR. The leptin, IL-6, IL-8 and matrix metalloproteinase (MMP)-1 levels were measured by ELISA. Leptin, the leptin receptor (Ob-R), GR and GILZ expression levels were analyzed by western blotting and/or RT-qPCR.
  
  
  
  (1) The glucocorticoid prednisolone and the mineralocorticoid aldosterone induced GILZ expression dose-dependently in OA synovial fibroblasts, through GR but not MR. Similar effects on leptin and Ob-R were observed: leptin secretion and Ob-R expression were also induced by prednisolone and aldosterone through GR; (2) GILZ silencing experiments demonstrated that GILZ was involved in the glucocorticoid-induced and mineralocorticoid-induced leptin secretion and Ob-R expression in OA synovial fibroblasts; and (3) GILZ inhibition did not alter the production of pro-inflammatory cytokines by OA synovial fibroblast or the anti-inflammatory properties of glucocorticoids.
  
  
  
  The absence of GILZ prevents corticoid-induced leptin and Ob-R expression without affecting the anti-inflammatory properties of glucocorticoids in OA synovial fibroblasts. Mineralocorticoids also induce leptin and Ob-R expression through GILZ.
authors.affiliation: Laboratory of Rheumatology, Arthropôle, GIGA Research, University and CHU of Liège, Liège, Belgium. olivier.malaise@chu.ulg.ac.be.
authors.forename: Olivier
authors.initials: O
authors.lastname: Malaise
authors.affiliation: Laboratory of Rheumatology, Arthropôle, GIGA Research, University and CHU of Liège, Liège, Belgium.
authors.forename: Biserka
authors.initials: B
authors.lastname: Relic
authors.affiliation: Laboratory of Rheumatology, Arthropôle, GIGA Research, University and CHU of Liège, Liège, Belgium.
authors.forename: Edith
authors.initials: E
authors.lastname: Charlier
authors.affiliation: Laboratory of Rheumatology, Arthropôle, GIGA Research, University and CHU of Liège, Liège, Belgium.
authors.forename: Mustapha
authors.initials: M
authors.lastname: Zeddou
authors.affiliation: Laboratory of Rheumatology, Arthropôle, GIGA Research, University and CHU of Liège, Liège, Belgium.
authors.forename: Sophie
authors.initials: S
authors.lastname: Neuville
authors.affiliation: Laboratory of Rheumatology, Arthropôle, GIGA Research, University and CHU of Liège, Liège, Belgium.
authors.forename: Céline
authors.initials: C
authors.lastname: Deroyer
authors.affiliation: Department of Orthopedic Surgery, CHU of Liège, Liège, Belgium.
authors.forename: Philippe
authors.initials: P
authors.lastname: Gillet
authors.affiliation: Laboratory of Gastroenterology, GIGA Research, University and CHU of Liège, Liège, Belgium.
authors.forename: Edouard
authors.initials: E
authors.lastname: Louis
authors.affiliation: Laboratory of Rheumatology, Arthropôle, GIGA Research, University and CHU of Liège, Liège, Belgium.
authors.forename: Michel G
authors.initials: MG
authors.lastname: Malaise
authors.affiliation: Laboratory of Rheumatology, Arthropôle, GIGA Research, University and CHU of Liège, Liège, Belgium.
authors.forename: Dominique
authors.initials: D
authors.lastname: de Seny
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000450:Aldosterone / Q000494:pharmacology; D015153:Blotting, Western; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D020738:Leptin / Q000096:biosynthesis*; D008297:Male; D008875:Middle Aged; D008901:Mineralocorticoids / Q000494:pharmacology; D020370:Osteoarthritis, Knee / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D011239:Prednisolone / Q000494:pharmacology; D000070918:Synoviocytes / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D005938:Glucocorticoids; D020738:Leptin; D008901:Mineralocorticoids; C404226:TSC22D3 protein, human; D014157:Transcription Factors; D000450:Aldosterone; D011239:Prednisolone
keywords: GILZ; Glucocorticoids; Leptin; Mineralocorticoids; Osteoarthritis; Synovial fibroblasts