PMID- 15468069
OWN - NLM
STAT- MEDLINE
DCOM- 20050601
LR  - 20091119
IS  - 0021-9541 (Print)
IS  - 0021-9541 (Linking)
VI  - 203
IP  - 2
DP  - 2005 May
TI  - TGF-beta-induced expression of tissue inhibitor of metalloproteinases-3 gene in 
      chondrocytes is mediated by extracellular signal-regulated kinase pathway and Sp1 
      transcription factor.
PG  - 345-52
AB  - Transforming growth factor (TGF-beta1) is a potent inducer of chondrogenesis and 
      stimulant of cartilage extracellular matrix (ECM) synthesis. Tissue inhibitor of 
      metalloproteinases-3 (TIMP-3) is located in ECM and is the major inhibitor of 
      matrix metalloproteinases (MMPs) and aggrecanase, the principal enzymes 
      implicated in collagen and aggrecan degradation in arthritis. We investigated the 
      role of extracellular-signal-regulated kinase (ERK)-mitogen-activated protein 
      kinases (MAPK) and Sp1 transcription factor in TGF-beta-induced TIMP-3 gene in 
      chondrocytes and chondrosarcoma cells. TGF-beta time-dependently induced a 
      sustained phosphorylation of ERK-MAPKs in primary human or bovine chondrocytes. 
      Inhibitors of this pathway, PD98059 and U0126, downregulated TGF-beta-induced 
      expression of TIMP-3 RNA and protein. Since the ERKs can phosphorylate Sp1, and 
      the promoter of human TIMP-3 gene contains four Sp1-binding sites, we 
      investigated whether Sp1 is a downstream target of this pathway. Mithramycin and 
      WP631, the agents that prevent binding of Sp1 to its consensus site, 
      downregulated TGF-beta-inducible TIMP-3 expression. Indeed, mithramycin blocked 
      TGF-beta-stimulated Sp1 binding activity. Transfection of cytomegalovirus (CMV) 
      promoter-Sp1 plasmid increased TIMP-3 promoter (-940 to +376)-driven luciferase 
      activity. Depletion of Sp1 by transfection of an antisense phosphorothioate 
      oligonucleotide suppressed TGF-beta-induced TIMP-3 protein expression, while its 
      sense homolog had no effect. These results suggest that activation of ERK-MAPK 
      pathway and Sp1 transcription factor play a pivotal role in the induction of 
      TIMP-3 by TGF-beta in chondrocytes.
CI  - Copyright 2004 Wiley-Liss, Inc.
FAU - Qureshi, Hamid Yaqoob
AU  - Qureshi HY
AD  - Department of Medicine and Centre de Recherche du Centre Hospitalier de 
      l'Universite de Montreal (CRCHUM), Montreal, Quebec, Canada.
FAU - Sylvester, Judith
AU  - Sylvester J
FAU - El Mabrouk, Mohammed
AU  - El Mabrouk M
FAU - Zafarullah, Muhammad
AU  - Zafarullah M
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Cell Physiol
JT  - Journal of cellular physiology
JID - 0050222
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Oligodeoxyribonucleotides, Antisense)
RN  - 0 (Protein Synthesis Inhibitors)
RN  - 0 (Sp1 Transcription Factor)
RN  - 0 (Tissue Inhibitor of Metalloproteinase-3)
RN  - 0 (Transforming Growth Factor beta)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
SB  - IM
MH  - Animals
MH  - Binding Sites/drug effects/physiology
MH  - Cartilage/cytology/drug effects/*metabolism
MH  - Cattle
MH  - Cells, Cultured
MH  - Chondrocytes/drug effects/*metabolism
MH  - Chondrogenesis/drug effects/physiology
MH  - Enzyme Inhibitors/pharmacology
MH  - Extracellular Matrix/metabolism
MH  - Extracellular Signal-Regulated MAP Kinases/*metabolism
MH  - Gene Expression Regulation/genetics
MH  - Gene Expression Regulation, Enzymologic/drug effects/physiology
MH  - Genetic Vectors/genetics
MH  - Humans
MH  - Oligodeoxyribonucleotides, Antisense/genetics
MH  - Phosphorylation/drug effects
MH  - Promoter Regions, Genetic/genetics
MH  - Protein Synthesis Inhibitors/pharmacology
MH  - Regeneration/drug effects/physiology
MH  - Sp1 Transcription Factor/*metabolism
MH  - Tissue Inhibitor of Metalloproteinase-3/*metabolism
MH  - Transforming Growth Factor beta/*metabolism/pharmacology
MH  - Tumor Cells, Cultured
EDAT- 2004/10/07 09:00
MHDA- 2005/06/02 09:00
CRDT- 2004/10/07 09:00
PHST- 2004/10/07 09:00 [pubmed]
PHST- 2005/06/02 09:00 [medline]
PHST- 2004/10/07 09:00 [entrez]
AID - 10.1002/jcp.20228 [doi]
PST - ppublish
SO  - J Cell Physiol. 2005 May;203(2):345-52. doi: 10.1002/jcp.20228.