title: Geranylgeranyl-pyrophosphate regulates secretion of pentraxin 3 and monocyte chemoattractant protein-1 from rheumatoid fibroblast-like synoviocytes in distinct manners.
abstract: OBJECTIVE
  We previously reported that 10 mg/day of simvastatin significantly reduced clinical scores of rheumatoid arthritis (RA) in active RA patients with hypercholesterolemia. In this study, we have investigated the mechanism by which simvastatin inhibits the production of the mediators of inflammation, such as pentraxin 3 (PTX3) and monocyte chemoattractant protein-1 (MCP-1), from fibroblast-like synoviocytes (FLS) derived from patients with RA.
  
  
  METHODS
  FLS from RA patients were cultured with 0-10 μM simvastatin for 24 h. ELISA and real-time PCR were used to quantitate the protein level and the mRNA level of PTX3 and MCP-1, respectively.
  
  
  RESULTS
  Simvastatin both reduced the secretion of PTX3 and MCP-1 in FLS cultures and inhibited their mRNA expression in these cells. The effects of simvastatin were all completely reversed in the presence of mevalonic acid or geranylgeranylpyrophosphate, but not in the presence of farnesyl-pyrophosphate. The geranylgeranyl transferase inhibitor GGTI-298 and the Rho kinase inhibitor Y-27632 inhibited the production of PTX3 but not of MCP-1.
  
  
  CONCLUSIONS
  Although simvastatin inhibited the production of PTX3 and MCP-1 in RA FLS, the mechanisms were quite different. It inhibits PTX3 production in a Rho-dependent manner but MCP-1 production in a Rho-independent manner. These results shed light on novel aspects of the anti-inflammatory mechanisms of simvastatin and may prove its important role in the treatment of rheumatic diseases.
authors.affiliation: Department of Rheumatology and Applied Immunology, Saitama Medical University, Saitama, Japan. yokotak@saitama-med.ac.jp
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Yokota
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Miyoshi
authors.forename: Kojiro
authors.initials: K
authors.lastname: Sato
authors.forename: Yu
authors.initials: Y
authors.lastname: Asanuma
authors.forename: Yuji
authors.initials: Y
authors.lastname: Akiyama
authors.forename: Toshihide
authors.initials: T
authors.lastname: Mimura
mesh_terms: D000577:Amides / Q000494:pharmacology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000473:pathology; D001549:Benzamides / Q000494:pharmacology; D002097:C-Reactive Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008798:Mevalonic Acid / Q000494:pharmacology; D011106:Polyisoprenyl Phosphates / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D000683:Serum Amyloid P-Component / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012717:Sesquiterpenes / Q000494:pharmacology; D019821:Simvastatin / Q000494:pharmacology*; D013583:Synovial Membrane / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000099153:Pentraxins
chemical_list: D000577:Amides; D001549:Benzamides; D002097:C-Reactive Protein; D018932:Chemokine CCL2; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008798:Mevalonic Acid; D011106:Polyisoprenyl Phosphates; D011725:Pyridines; D012333:RNA, Messenger; D000683:Serum Amyloid P-Component; D012717:Sesquiterpenes; D019821:Simvastatin; D000099153:Pentraxins; C102521:GGTI 298; C108830:Y 27632; C004808:farnesyl pyrophosphate; C002963:geranylgeranyl pyrophosphate