PMID- 14730623
OWN - NLM
STAT- MEDLINE
DCOM- 20040217
LR  - 20131121
IS  - 0004-3591 (Print)
IS  - 0004-3591 (Linking)
VI  - 50
IP  - 1
DP  - 2004 Jan
TI  - Proline-rich tyrosine kinase 2 and Src kinase signaling transduce monosodium 
      urate crystal-induced nitric oxide production and matrix metalloproteinase 3 
      expression in chondrocytes.
PG  - 247-58
AB  - OBJECTIVE: Articular deposition of monosodium urate monohydrate (MSU) crystals 
      may promote cartilage and bone erosion. Therefore, the aim of this study was to 
      determine how MSU crystals stimulate chondrocytes. METHODS: Nitric oxide (NO) 
      release, and expression of inducible nitric oxide synthase (iNOS) and matrix 
      metalloproteinase 3 (MMP-3) were assessed in cultured chondrocytes treated with 
      MSU. MSU-induced functional signaling by specific protein kinases (p38, Src, and 
      the focal adhesion kinase [FAK] family members proline-rich tyrosine kinase 2 
      [Pyk-2] and FAK) was also examined using selective pharmacologic inhibitors and 
      transfection of kinase mutants. RESULTS: MSU induced MMP-3 and iNOS expression 
      and NO release in chondrocytes in a p38-dependent manner that did not require 
      interleukin-1 (IL-1), as demonstrated by using IL-1 receptor antagonist. MSU 
      induced rapid tyrosine phosphorylation of Pyk-2 and FAK, their adaptor protein 
      paxillin, and interacting kinase c-Src. Pyk-2 and c-Src signaling both mediated 
      p38 MAPK activation in response to MSU. Pyk-2 and c-Src signaling played a major 
      role in transducing MSU-induced NO production and MMP-3 expression. But, despite 
      the observed FAK phosphorylation, a selective pharmacologic FAK inhibitor and a 
      FAK dominant-negative mutant both failed to block MSU-induced NO release or MMP-3 
      expression in parallel experiments. CONCLUSION: In chondrocytes, MSU crystals 
      activate a signaling kinase cascade typically employed by adhesion receptors that 
      involves upstream Src and FAK family activation and downstream p38 activation. In 
      this cascade, Pyk-2, Src, and p38 kinases transduce MSU-induced NO production and 
      MMP-3 expression. Our results identify Pyk-2 and c-Src as novel sites for 
      potential therapeutic intervention in cartilage degradation in chronic gout.
FAU - Liu, Ru
AU  - Liu R
AD  - VA Medical Center and University of California, San Diego, CA 92161, USA.
FAU - Liote, Frederic
AU  - Liote F
FAU - Rose, David M
AU  - Rose DM
FAU - Merz, Denise
AU  - Merz D
FAU - Terkeltaub, Robert
AU  - Terkeltaub R
LA  - eng
GR  - HL-61731/HL/NHLBI NIH HHS/United States
GR  - P01-AG07996/AG/NIA NIH HHS/United States
GR  - R03-AR-49416-10/AR/NIAMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Arthritis Rheum
JT  - Arthritis and rheumatism
JID - 0370605
RN  - 268B43MJ25 (Uric Acid)
RN  - 31C4KY9ESH (Nitric Oxide)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase Type II)
RN  - EC 2.7.10.1 (Protein-Tyrosine Kinases)
RN  - EC 2.7.10.2 (Focal Adhesion Kinase 2)
RN  - EC 2.7.10.2 (Focal Adhesion Protein-Tyrosine Kinases)
RN  - EC 2.7.10.2 (src-Family Kinases)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
RN  - EC 3.4.24.17 (Matrix Metalloproteinase 3)
SB  - IM
MH  - Animals
MH  - Cattle
MH  - Cells, Cultured
MH  - Chondrocytes/cytology/*enzymology
MH  - Crystallization
MH  - Focal Adhesion Kinase 2
MH  - Focal Adhesion Protein-Tyrosine Kinases
MH  - Gene Expression Regulation, Enzymologic
MH  - Matrix Metalloproteinase 3/genetics/*metabolism
MH  - Mitogen-Activated Protein Kinases/metabolism
MH  - Nitric Oxide/*metabolism
MH  - Nitric Oxide Synthase/genetics/metabolism
MH  - Nitric Oxide Synthase Type II
MH  - Protein-Tyrosine Kinases/genetics/*metabolism
MH  - Signal Transduction/physiology
MH  - Uric Acid/chemistry/*metabolism
MH  - p38 Mitogen-Activated Protein Kinases
MH  - src-Family Kinases/*metabolism
EDAT- 2004/01/20 05:00
MHDA- 2004/02/18 05:00
CRDT- 2004/01/20 05:00
PHST- 2004/01/20 05:00 [pubmed]
PHST- 2004/02/18 05:00 [medline]
PHST- 2004/01/20 05:00 [entrez]
AID - 10.1002/art.11486 [doi]
PST - ppublish
SO  - Arthritis Rheum. 2004 Jan;50(1):247-58. doi: 10.1002/art.11486.