Document Detail

Macrophage migration inhibitory factor up-regulates matrix metalloproteinase-9 and -13 in rat osteoblasts. Relevance to intracellular signaling pathways.
MedLine Citation:
PMID:  11751895     Owner:  NLM     Status:  MEDLINE    
Neutral matrix metalloproteinases (MMPs) play an important role in bone matrix degradation accompanied by bone remodeling. We herein show for the first time that macrophage migration inhibitory factor (MIF) up-regulates MMP-13 (collagenase-3) mRNA of rat calvaria-derived osteoblasts. The mRNA up-regulation was seen at 3 h in response to MIF (10 microg/ml), reached the maximum level at 6-12 h, and returned to the basal level at 36 h. MMP-13 mRNA up-regulation was preceded by up-regulation of c-jun and c-fos mRNA. Tissue inhibitor of metalloproteinase (TIMP)-1 and MMP-9 (92-kDa type IV collagenase) were also up-regulated, but to a lesser extent. The MMP-13 mRNA up-regulation was significantly suppressed by genistein, herbimycin A and 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine. Similarly, a selective mitogen-activated protein kinase (MAPK) kinase (MEK)1/2 inhibitor (PD98059) and c-jun/activator protein (AP)-1 inhibitor (curcumin) suppressed MMP-13 mRNA up-regulation induced by MIF. The mRNA levels of c-jun and c-fos in response to MIF were also inhibited by PD98059. Consistent with these results, MIF stimulated phosphorylation of tyrosine, autophosphorylation of Src, activation of Ras, activation of extracellular signal-regulated kinases (ERK) 1/2, a MAPK, but not c-Jun N-terminal kinase or p38, and phosphorylation of c-Jun. Osteoblasts obtained from calvariae of newborn JunAA mice, defective in phosphorylation of c-Jun, or newborn c-Fos knockout (Fos -/- ) mice, showed much less induction of MMP-13 with the addition of MIF than osteoblasts obtained from wild-type or littermate control mice. Taken together, these results suggest that MIF increases the MMP-13 mRNA level of rat osteoblasts via the Src-related tyrosine kinase-, Ras-, ERK1/2-, and AP-1-dependent pathway.
Shin Onodera; Jun Nishihira; Kazuya Iwabuchi; Yoshikazu Koyama; Kazuhiko Yoshida; Sakae Tanaka; Akio Minami
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2001-12-20
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  277     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2002 Mar 
Date Detail:
Created Date:  2002-03-04     Completed Date:  2002-04-15     Revised Date:  2013-06-03    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  7865-74     Citation Subset:  IM    
Department of Orthopaedics, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
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MeSH Terms
Bone and Bones / metabolism
Collagenases / biosynthesis*,  metabolism
Dose-Response Relationship, Drug
Enzyme Inhibitors / pharmacology
Fibroblasts / enzymology,  metabolism
Flavonoids / pharmacology
Genes, Dominant
MAP Kinase Kinase 1
MAP Kinase Kinase 2
Macrophage Migration-Inhibitory Factors / metabolism*
Matrix Metalloproteinase 13
Matrix Metalloproteinase 9 / biosynthesis*
Mitogen-Activated Protein Kinase Kinases / metabolism
Mitogen-Activated Protein Kinases / metabolism
Osteoblasts / enzymology*,  metabolism*
Protein Binding
Protein-Serine-Threonine Kinases / metabolism
Protein-Tyrosine Kinases / metabolism
Proto-Oncogene Proteins c-jun / metabolism
RNA, Messenger / metabolism
Recombinant Proteins / metabolism
Signal Transduction*
Time Factors
Transcription Factor AP-1 / metabolism
Tyrosine / metabolism
p38 Mitogen-Activated Protein Kinases
src-Family Kinases / metabolism
Reg. No./Substance:
0/2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; 0/Enzyme Inhibitors; 0/Flavonoids; 0/Macrophage Migration-Inhibitory Factors; 0/Proto-Oncogene Proteins c-jun; 0/RNA, Messenger; 0/Recombinant Proteins; 0/Transcription Factor AP-1; 55520-40-6/Tyrosine; EC Kinases; EC Kinases; EC Kinases; EC Protein Kinases; EC Mitogen-Activated Protein Kinases; EC Kinase Kinase 1; EC Kinase Kinase 2; EC Protein Kinase Kinases; EC 3.4.24.-/Collagenases; EC 3.4.24.-/Matrix Metalloproteinase 13; EC 3.4.24.-/Mmp13 protein, rat; EC Metalloproteinase 9

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