PMID- 20178133
OWN - NLM
STAT- MEDLINE
DCOM- 20100628
LR  - 20100614
IS  - 1529-0131 (Electronic)
IS  - 0004-3591 (Linking)
VI  - 62
IP  - 6
DP  - 2010 Jun
TI  - Aurothiomalate inhibits cyclooxygenase 2, matrix metalloproteinase 3, and 
      interleukin-6 expression in chondrocytes by increasing MAPK phosphatase 1 
      expression and decreasing p38 phosphorylation: MAPK phosphatase 1 as a novel 
      target for antirheumatic drugs.
PG  - 1650-9
LID - 10.1002/art.27409 [doi]
AB  - OBJECTIVE: Aurothiomalate is a disease-modifying antirheumatic drug that 
      suppresses inflammation and retards cartilage degradation and bone erosion in 
      arthritis. The molecular mechanisms of action of aurothiomalate are not known in 
      detail. MAPK pathways are major signaling pathways in inflammation that regulate 
      the production of many inflammatory and destructive factors in arthritis. The 
      purpose of the present study was to investigate the effects of aurothiomalate on 
      the activity of p38 MAPK and on the expression of MAPK phosphatase 1 (MKP-1), 
      cyclooxygenase 2 (COX-2), matrix metalloproteinase 3 (MMP-3), and interleukin-6 
      (IL-6) in immortalized murine H4 chondrocytes and in intact human and murine 
      cartilage. METHODS: Protein expression was examined by Western blotting or by 
      enzyme-linked immunosorbent assay, and messenger RNA (mRNA) expression was 
      examined by real-time reverse transcription-polymerase chain reaction analysis. 
      The mediator role of MKP-1 was investigated by using small interfering RNA 
      (siRNA) methods to down-regulated MKP-1 expression in chondrocytes in culture and 
      by comparing the responses in intact cartilage from MKP-1-deficient and wild-type 
      mice. The effects of aurothiomalate were also confirmed in human rheumatoid 
      cartilage by using tissue samples obtained at the time of total knee replacement 
      surgery. RESULTS: Aurothiomalate inhibited IL-1beta-induced COX-2 expression and 
      prostaglandin E(2) production by destabilizing COX-2 mRNA, as did the p38 MAPK 
      inhibitor SB203580. Interestingly, aurothiomalate also increased the expression 
      of MKP-1 and reduced the IL-1beta-induced phosphorylation of p38 MAPK. Knockdown 
      of MKP-1 by siRNA significantly impaired the ability of aurothiomalate to inhibit 
      the phosphorylation of p38 MAPK and the expression of COX-2, MMP-3, and IL-6. 
      Likewise, aurothiomalate reduced COX-2, MMP-3, and IL-6 expression in articular 
      cartilage from patients with rheumatoid arthritis, as well as in articular 
      cartilage from wild-type mice but not from MKP-1(-/-) mice. CONCLUSION: Our 
      findings indicate a novel mechanism for the antiinflammatory and antierosive 
      actions of aurothiomalate, through increased expression of MKP-1, which leads to 
      reduced activation of p38 MAPK and suppressed expression of COX-2, MMP-3, and 
      IL-6. The results suggest that manipulation of MKP-1 levels is a promising new 
      mechanism to be directed in the search and development of novel antiinflammatory 
      and antierosive compounds that have the good efficacy of gold compounds but not 
      their toxicity.
FAU - Nieminen, Riina
AU  - Nieminen R
AD  - The Immunopharmacology Research Group, University of Tampere Medical School and 
      Tampere University Hospital, Tampere, Finland.
FAU - Korhonen, Riku
AU  - Korhonen R
FAU - Moilanen, Teemu
AU  - Moilanen T
FAU - Clark, Andrew R
AU  - Clark AR
FAU - Moilanen, Eeva
AU  - Moilanen E
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Arthritis Rheum
JT  - Arthritis and rheumatism
JID - 0370605
RN  - 0 (Antirheumatic Agents)
RN  - 0 (Interleukin-6)
RN  - 0 (RNA, Messenger)
RN  - 12244-57-4 (Gold Sodium Thiomalate)
RN  - EC 1.14.99.1 (Cyclooxygenase 2)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
RN  - EC 3.1.3.48 (Dual Specificity Phosphatase 1)
RN  - EC 3.4.24.17 (Matrix Metalloproteinase 3)
SB  - IM
MH  - Analysis of Variance
MH  - Animals
MH  - Antirheumatic Agents/pharmacology
MH  - Blotting, Western
MH  - Cartilage, Articular/drug effects/*metabolism
MH  - Cells, Cultured
MH  - Chondrocytes/drug effects/*metabolism
MH  - Cyclooxygenase 2/genetics/*metabolism
MH  - Dual Specificity Phosphatase 1/genetics/*metabolism
MH  - Enzyme-Linked Immunosorbent Assay
MH  - Female
MH  - Gene Expression Regulation
MH  - Gold Sodium Thiomalate/*pharmacology
MH  - Humans
MH  - Interleukin-6/genetics/*metabolism
MH  - Matrix Metalloproteinase 3/genetics/*metabolism
MH  - Mice
MH  - Mice, Transgenic
MH  - Phosphorylation/drug effects/genetics
MH  - RNA Interference
MH  - RNA, Messenger/genetics/metabolism
MH  - Radioimmunoassay
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - p38 Mitogen-Activated Protein Kinases/genetics/*metabolism
EDAT- 2010/02/24 06:00
MHDA- 2010/06/29 06:00
CRDT- 2010/02/24 06:00
PHST- 2010/02/24 06:00 [entrez]
PHST- 2010/02/24 06:00 [pubmed]
PHST- 2010/06/29 06:00 [medline]
AID - 10.1002/art.27409 [doi]
PST - ppublish
SO  - Arthritis Rheum. 2010 Jun;62(6):1650-9. doi: 10.1002/art.27409.