Signaling pathways implicated in oncostatin M-induced aggrecanase-1 and matrix metalloproteinase-13 expression in human articular chondrocytes.
Molecular mechanisms of oncostatin M (OSM)-stimulated cartilage extracellular matrix catabolism and signaling pathways were investigated in human arthritic chondrocytes. OSM, alone or with Interleukin-1 (IL-1beta), increased glycosaminoglycan release and induced ADAMTS-4 and MMP-13 protein expression in human cartilage explants. OSM dose- and time-dependently increased ADAMTS-4 mRNA and MMP-13 protein expression in human femoral head chondrocytes. Extracellular signal-regulated kinases (ERK1/2)-MAPK pathway inhibitor, U0126, down-regulated ADAMTS-4 and MMP-13 induction by OSM. Janus kinase 2 (JAK2) inhibitor, AG490, suppressed OSM-induced ADAMTS-4 mRNA expression but did not affect MMP-13 levels while JAK3 pharmacological inhibitor and siRNA transfection suppressed both. Parthenolide, a signal transducer and activator of transcription (STAT1 and STAT3) phosphorylation inhibitor, reduced OSM-induced ADAMTS-4 and MMP-13 gene expression and prevented STAT1/3 DNA binding activity. Additionally, OSM-enhanced ADAMTS-4 mRNA and MMP-13 expression was down-regulated by phosphatidylinositol 3-kinase (PI3K) and Akt/PKB inhibitors, LY294002 and NL-71-101. Furthermore, JAK3 inhibition time-dependently down-regulated Akt but not ERK1/2 phosphorylation suggesting that Akt is a downstream target of JAK3. These results suggest that OSM-stimulated ADAMTS-4 and MMP-13 expression is mediated by ERK1/2, JAK3/STAT1/3 and PI3K/Akt and by cross talk between these pathways. The inhibitors of these cascades could block OSM-evoked degeneration of cartilage by ADAMTS-4 and MMP-13.
El Mabrouk
Mohammed
M
Department of Medicine and Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CR-CHUM), K-5255 Mailloux, Notre-Dame Hospital, 1560 Sherbrooke E. Montreal, Quebec, Canada H2L 4M1.
Sylvester
Judith
J
Zafarullah
Muhammad
M
D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism*; D000071121:ADAMTS4 Protein; D001158:Arteries / Q000187:drug effects / Q000201:enzymology; D002356:Cartilage / Q000187:drug effects / Q000201:enzymology; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects* / Q000201:enzymology*; D004247:DNA / Q000378:metabolism; D015536:Down-Regulation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D053612:Janus Kinases / Q000235:genetics / Q000378:metabolism; D053509:Matrix Metalloproteinase 13 / Q000235:genetics / Q000378:metabolism*; D053683:Oncostatin M / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011348:Procollagen N-Endopeptidase / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D050791:STAT Transcription Factors / Q000378:metabolism; D012717:Sesquiterpenes / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*
D007375:Interleukin-1; D034741:RNA, Small Interfering; D050791:STAT Transcription Factors; D012717:Sesquiterpenes; D053683:Oncostatin M; C002669:parthenolide; D004247:DNA; D019869:Phosphatidylinositol 3-Kinases; D053612:Janus Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D051722:ADAM Proteins; D053509:Matrix Metalloproteinase 13; D011348:Procollagen N-Endopeptidase; D000071121:ADAMTS4 Protein; C000603918:ADAMTS4 protein, human