PMID- 21345291
OWN - NLM
STAT- MEDLINE
DCOM- 20110503
LR  - 20171116
IS  - 0392-856X (Print)
IS  - 0392-856X (Linking)
VI  - 29
IP  - 1
DP  - 2011 Jan-Feb
TI  - Geranylgeranyl-pyrophosphate regulates secretion of pentraxin 3 and monocyte 
      chemoattractant protein-1 from rheumatoid fibroblast-like synoviocytes in 
      distinct manners.
PG  - 43-9
AB  - OBJECTIVES: 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 muM 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.
FAU - Yokota, Kazuhiro
AU  - Yokota K
AD  - Department of Rheumatology and Applied Immunology, Saitama Medical University, 
      Saitama, Japan. yokotak@saitama-med.ac.jp
FAU - Miyoshi, Fumihiko
AU  - Miyoshi F
FAU - Sato, Kojiro
AU  - Sato K
FAU - Asanuma, Yu
AU  - Asanuma Y
FAU - Akiyama, Yuji
AU  - Akiyama Y
FAU - Mimura, Toshihide
AU  - Mimura T
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20110223
PL  - Italy
TA  - Clin Exp Rheumatol
JT  - Clinical and experimental rheumatology
JID - 8308521
RN  - 0 (Amides)
RN  - 0 (Benzamides)
RN  - 0 (Chemokine CCL2)
RN  - 0 (GGTI 298)
RN  - 0 (Hydroxymethylglutaryl-CoA Reductase Inhibitors)
RN  - 0 (Polyisoprenyl Phosphates)
RN  - 0 (Pyridines)
RN  - 0 (RNA, Messenger)
RN  - 0 (Serum Amyloid P-Component)
RN  - 0 (Sesquiterpenes)
RN  - 138381-45-0 (Y 27632)
RN  - 148591-49-5 (PTX3 protein)
RN  - 79W6B01D07 (farnesyl pyrophosphate)
RN  - 9007-41-4 (C-Reactive Protein)
RN  - AGG2FN16EV (Simvastatin)
RN  - N21T0D88LX (geranylgeranyl pyrophosphate)
RN  - S5UOB36OCZ (Mevalonic Acid)
SB  - IM
MH  - Amides/pharmacology
MH  - Arthritis, Rheumatoid/*drug therapy/pathology
MH  - Benzamides/pharmacology
MH  - C-Reactive Protein/antagonists & inhibitors/genetics/*metabolism
MH  - Cells, Cultured
MH  - Chemokine CCL2/antagonists & inhibitors/genetics/*metabolism
MH  - Fibroblasts/drug effects/metabolism/pathology
MH  - Gene Expression/drug effects
MH  - Humans
MH  - Hydroxymethylglutaryl-CoA Reductase Inhibitors/*pharmacology
MH  - Mevalonic Acid/pharmacology
MH  - Polyisoprenyl Phosphates/*pharmacology
MH  - Pyridines/pharmacology
MH  - RNA, Messenger/metabolism
MH  - Serum Amyloid P-Component/antagonists & inhibitors/genetics/*metabolism
MH  - Sesquiterpenes/pharmacology
MH  - Simvastatin/*pharmacology
MH  - Synovial Membrane/drug effects/metabolism/pathology
EDAT- 2011/02/25 06:00
MHDA- 2011/05/04 06:00
CRDT- 2011/02/25 06:00
PHST- 2010/04/20 00:00 [received]
PHST- 2010/10/11 00:00 [accepted]
PHST- 2011/02/25 06:00 [entrez]
PHST- 2011/02/25 06:00 [pubmed]
PHST- 2011/05/04 06:00 [medline]
AID - 3888 [pii]
PST - ppublish
SO  - Clin Exp Rheumatol. 2011 Jan-Feb;29(1):43-9. Epub 2011 Feb 23.