title: Tumor necrosis factor-α induces ADAMTS-4 expression in human osteoarthritis chondrocytes.
abstract: Tumor necrosis factor (TNF)-α and a disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS-4) are important in osteoarthritis (OA) cartilage degradation. In the present study, we explored the interaction between the two proteins by examining the effect of TNF-α on ADAMTS-4 expression and activity in osteoarthritic chondrocytes. Human osteoarthritic chondrocytes were treated with TNF-α in different concentrations (5, 15, 30, 45 and 60 ng/ml) for different lengths of time (1, 6, 12, 18 and 24 h) with or without the TNF receptor 1 (TNFR1) inhibitor SPD304 or different kinase inhibitors. TNF-α increased the ADAMTS-4 mRNA level in a statistically significant dose- and time-dependent manner within 18 h, which was reflected in the dose-dependent induction of the ADAMTS-4 promoter activity, ADAMTS-4 protein expression and ADAMTS-4 activity. SPD304 (50 µM) and p38 mitogen-activated protein kinase (MAPK) siRNA and inhibitor PD169316 (25 µM) completely eradicated the promoting effect of TNF-α on ADAMTS-4 expression and activity. TNF-α induces ADAMTS-4 expression and activity in human osteoarthritic chondrocytes at the transcriptional level via TNFR1 by a p38 MAPK-dependent mechanism. To the best of our knowledge, this is the first evidence of crosstalk between TNF-α and ADAMTS-4 in relation to OA cartilage degradation, which adds novel insight into the pathophysiology of OA and cartilage degradation.
authors.affiliation: Department of Urology, Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China.
authors.forename: Juan
authors.initials: J
authors.lastname: Xue
authors.forename: Jianlong
authors.initials: J
authors.lastname: Wang
authors.forename: Qiang
authors.initials: Q
authors.lastname: Liu
authors.forename: Aijing
authors.initials: A
authors.lastname: Luo
mesh_terms: D051722:ADAM Proteins / Q000235:genetics* / Q000378:metabolism; D000071121:ADAMTS4 Protein; D015153:Blotting, Western; D019902:Chondrocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D010003:Osteoarthritis / Q000201:enzymology / Q000235:genetics* / Q000473:pathology*; D011348:Procollagen N-Endopeptidase / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; D051722:ADAM Proteins; D011348:Procollagen N-Endopeptidase; D000071121:ADAMTS4 Protein; C000603918:ADAMTS4 protein, human
keywords: osteoarthritis; tumor  necrosis  factor-α; chondrocytes; p38 mitogen-activated protein kinase