Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:3.4.24.3 (
collagenase
)
18,340
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
The effect of expression of c-fos gene on proteoglycan synthesis, one of the important markers of cartilage metabolism, was examined by introducing the c-fos DNA into
HCS
2/8 chondrocytes. The [35S]sulfate incorporation into proteoglycan was decreased in the c-fos transfectants expressing exogenous c-fos mRNA, when compared to a control transfectant. A significant increase in transcription of MMP-3 with the suppressed transcription of aggrecan and TIMP-1 were also observed in the c-fos transfectants. Moreover, analysis of the effect of AP-1 proteins on the
collagenase
and TIMP-1 promoters in gastric carcinoma KKLS cells revealed that c-Fos combined with any of the Jun-related proteins failed to stimulate the TIMP-1 promoter, though
collagenase
promoter was effectively activated by any Fos/Jun-related protein heterocomplex. These findings indicate that the c-fos expression may govern the cartilage metabolism and hence may play an important role in the pathogenesis of joint destruction in arthritis.
...
PMID:Expression of c-fos gene inhibits proteoglycan synthesis in transfected chondrocyte. 860 60
Matrix metalloproteinase-1 (
MMP-1
,
collagenase
-1) plays a pivotal role in the process of joint destruction in degenerative joint diseases. We have examined the regulation of
MMP-1
production in human chondrocytic
HCS
-2/8 cells stimulated by tumor necrosis factor-alpha (TNF-alpha). In response to TNF-alpha,
MMP-1
is induced and actively released from
HCS
-2/8 cells. The induction of
MMP-1
expression correlates with activation of ERK1/2, MEK, and Raf-1, and is potently prevented by U0126, a selective inhibitor of MEK1/2 activation. In contrast, SB203580, a selective p38 mitogen-activated protein kinases (MAPK) inhibitor, had no effects on TNF-alpha-induced
MMP-1
release. A serine/threonine kinase, Akt was not activated in TNF-alpha-stimulated
HCS
-2/8 cells. TNF-alpha stimulated the production of PGE(2) in addition to
MMP-1
in
HCS
-2/8 cells. Exogenously added PGE(2) potently inhibited TNF-alpha-induced both
MMP-1
production and activation of ERK1/2. The effects of PGE(2) were mimicked by ONO-AE1-329, a selective EP4 receptor agonist but not by butaprost, a selective EP2 agonist. In contrast, blockade of endogenously produced PGE(2) signaling by ONO-AE3-208, a selective EP4 receptor antagonist, enhanced TNF-alpha-induced
MMP-1
production. Furthermore, the suppression of
MMP-1
production by exogenously added PGE(2) was reversed by ONO-AE3-208. Activation of EP4 receptor resulted in cAMP-mediated phosphorylation of Raf-1 on Ser259, a negative regulatory site, and blocked activation of Raf-1/MEK/ERK cascade. Taken together, these findings indicate that Raf-1/MEK/ERK signaling pathway plays a crucial role in the production of
MMP-1
in
HCS
-2/8 cells in response to TNF-alpha, and that the produced PGE(2) downregulates the expression of
MMP-1
by blockage of TNF-alpha-induced Raf-1 activation through EP4-PGE(2) receptor activation.
...
PMID:Prostaglandin E2 downregulates TNF-alpha-induced production of matrix metalloproteinase-1 in HCS-2/8 chondrocytes by inhibiting Raf-1/MEK/ERK cascade through EP4 prostanoid receptor activation. 1703 53
