title: Simvastatin inhibits cytokine-stimulated Cyr61 expression in osteoblastic cells: a therapeutic benefit for arthritis.
abstract: OBJECTIVE
  To examine the effects of proinflammatory cytokines on Cyr61 expression in osteoblastic cells and the modulatory action of simvastatin, to assess the role of CREB in Cyr61 induction, and to investigate the relationship of osteoblastic expression of Cyr61 to disease progression in experimental arthritis.
  
  
  METHODS
  Cyr61 expression and CREB phosphorylation at serine 133 were examined by Western blotting. Promoter activity of Cyr61 was assessed by luciferase assay with promoter deletion/mutagenesis and forced expression/gene silencing of CREB. Interaction between CREB and the Cyr61 promoter was evaluated by electrophoretic mobility shift assay and chromatin immunoprecipitation. CCL2 expression was examined by Northern blotting and enzyme-linked immunosorbent assay. In rats with collagen-induced arthritis (CIA), osteoblastic expression of Cyr61 was examined by immunohistochemistry, and disease progression was assessed by clinical, radiographic, and histologic examination.
  
  
  RESULTS
  In primary human osteoblasts and U2OS cells, Cyr61 expression stimulated by tumor necrosis factor α, interleukin-1β (IL-1β), oncostatin M (OSM), and other IL-6-family cytokines was suppressed by simvastatin. In U2OS cells, simvastatin inhibited OSM-induced CREB phosphorylation and CREB-DNA binding. Knockdown of CREB by short hairpin RNA reduced Cyr61 synthesis. OSM-induced Cyr61 promoter activation was dependent on CRE-CREB interaction and inhibited by simvastatin. Cyr61 enhanced CCL2 expression by U2OS cells. Intraarticular injection of simvastatin inhibited CIA progression and diminished the number of Cyr61+ osteoblasts and infiltrating macrophages.
  
  
  CONCLUSIONS
  Simvastatin inhibited cytokine-stimulated Cyr61 expression in osteoblastic cells and suppressed disease progression and osteoblastic expression of Cyr61 in inflammatory arthritis. This finding indicates that simvastatin may have potential as a therapeutic agent for inflammatory arthritis.
authors.affiliation: National Taiwan University, Taipei, Taiwan.
authors.forename: Sang-Heng
authors.initials: SH
authors.lastname: Kok
authors.forename: Kuo-Liang
authors.initials: KL
authors.lastname: Hou
authors.forename: Chi-Yuan
authors.initials: CY
authors.lastname: Hong
authors.forename: Juo-Song
authors.initials: JS
authors.lastname: Wang
authors.forename: Po-Chin
authors.initials: PC
authors.lastname: Liang
authors.forename: Cheng-Chi
authors.initials: CC
authors.lastname: Chang
authors.forename: Michael
authors.initials: M
authors.lastname: Hsiao
authors.forename: Hsiang
authors.initials: H
authors.lastname: Yang
authors.forename: Eddie Hsiang-Hua
authors.initials: EH
authors.lastname: Lai
authors.forename: Sze-Kwan
authors.initials: SK
authors.lastname: Lin
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D001169:Arthritis, Experimental / Q000188:drug therapy*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D055515:Cysteine-Rich Protein 61 / Q000378:metabolism*; D016207:Cytokines / Q000494:pharmacology*; D004195:Disease Models, Animal; D018450:Disease Progression; D006801:Humans; D007270:Injections, Intra-Articular; D008297:Male; D010006:Osteoblasts / Q000187:drug effects* / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019821:Simvastatin / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000924:Anticholesteremic Agents; C501848:CCN1 protein, human; D018932:Chemokine CCL2; D017362:Cyclic AMP Response Element-Binding Protein; D055515:Cysteine-Rich Protein 61; D016207:Cytokines; D019821:Simvastatin