6533b82ffe1ef96bd1295d55
RESEARCH PRODUCT
Induction of collagenase-3 (MMP-13) expression in human skin fibroblasts by three-dimensional collagen is mediated by p38 mitogen-activated protein kinase.
Veli-matti KähäriJyrki HeinoJyrki HeinoLaura RavantiCarlos López-otínsubject
MAPK/ERK pathwayIntegrinsReceptors CollagenSB 203580IntegrinDown-RegulationBiologyBiochemistryp38 Mitogen-Activated Protein KinasesCollagen receptorIntegrin alpha1beta1chemistry.chemical_compoundTransforming Growth Factor betaMatrix Metalloproteinase 13medicineHumansCollagenasesProtein kinase AMolecular BiologyDNA PrimersSkinBase SequenceKinaseTumor Necrosis Factor-alphaCell BiologyFibroblastsProtein-Tyrosine KinasesMolecular biologyEnzyme ActivationchemistryCalcium-Calmodulin-Dependent Protein KinasesCollagenasebiology.proteinCollagenMitogen-Activated Protein KinasesTyrosine kinasemedicine.drugInterleukin-1description
Collagenase-3 (matrix metalloproteinase-13, MMP-13) is a recently identified human MMP with an exceptionally wide substrate specificity and restricted tissue-specific expression. Here we show that MMP-13 expression is induced in normal human skin fibroblasts cultured within three-dimensional collagen gel resulting in production and proteolytic activation of MMP-13. Induction of MMP-13 mRNAs by collagen gel was potently inhibited by blocking antibodies against alpha1 and alpha2 integrin subunits and augmented by activating antibody against beta1 integrin subunit, indicating that both alpha1 beta1 and alpha2 beta1 integrins mediate the MMP-13-inducing cellular signal generated by three-dimensional collagen. Collagen-related induction of MMP-13 expression was dependent on tyrosine kinase activity, as it was abolished by treatment of fibroblasts with tyrosine kinase inhibitors genistein and herbimycin A. Contact of fibroblasts to three-dimensional collagen resulted in simultaneous activation of mitogen-activated protein kinases (MAPKs) in three distinct subgroups: extracellular signal-regulated kinase (ERK)1 and ERK2, Jun N-terminal kinase/stress-activated protein kinase, and p38. Induction of MMP-13 expression was inhibited by treatment of fibroblasts with a specific p38 inhibitor, SB 203580, whereas blocking the ERK1,2 pathway (Raf/MEK1,2/ERK1,2) by PD 98059, a selective inhibitor of MEK1,2 activation potently augmented MMP-13 expression. Furthermore, specific activation of ERK1,2 pathway by 12-O-tetradecanoylphorbol-13-acetate markedly suppressed MMP-13 expression in dermal fibroblasts in collagen gel. These results show that collagen-dependent induction of MMP-13 in dermal fibroblasts requires p38 activity, and is inhibited by activation of ERK1,2. Therefore, the balance between the activity of ERK1,2 and p38 MAPK pathways appears to be crucial in regulation of MMP-13 expression in dermal fibroblasts, suggesting that p38 MAPK may serve as a target for selective inhibition of collagen degradation, e.g. in chronic dermal ulcers.
year | journal | country | edition | language |
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1999-01-16 | The Journal of biological chemistry |