title: Induction of human ADAMTS-2 gene expression by IL-1α is mediated by a multiple crosstalk of MEK/JNK and PI3K pathways in osteoblast like cells.
abstract: Up-regulation of ADAMTS genes with proinflammatory cytokines is important for some pathological conditions such as osteoarthritis (OA) that is a disease based on ECM degradation in cartilage. IL-1α is a proinflammatory cytokine and important both to normal and pathophysiologic conditions in cartilage and bone. Effects of some proinflammatory cytokines such as TNF-α and IL-1β on the some members of ADAMTS family have been investigated in some chondrocyte tissues or cell lines. However the effect of the IL-1α on the expression of ADAMTS-2 and ADAMTS-3 gene expression in osteoblast like cell lines, remains unclear. Therefore, the aim of this study is to investigate the effect of IL-1α on ADAMTS-2 and ADAMTS-3 gene expression in osteoblast like cells, Saos-2 and MG-63. The present study, for the first time, demonstrated that IL-1α increases ADAMTS-2 and ADAMTS-3 gene expressions in both Saos-2 and MG-63 cells. Having correlation to mRNA induction, the upregulation of ADAMTS-2,-3 protein levels by IL-1α stimulation is also observed. The inhibition studies showed that this upregulation occurred at the level of transcription, and there was no effect of IL-1α on ADAMTS-2 mRNA half-life in Saos-2 cells. Transactivation potential of IL-1α on ADAMTS-2 promoter was investigated by transient transfection assay. Specifically, IL-1α strongly increased -658/+112 and -530/+112 ADAMTS-2 promoter constructs. Further, we analyzed signaling pathways involved in ADAMTS-2 induction. Pathway inhibition studies revealed that this upregulation depends on the activation of MEK, JNK and PI3K pathways. These findings suggested that IL-1α is a strong positive regulator of ADAMTS-2 and ADAMTS-3 expression. These findings would provide novel insight into the pathophysiology of OA.
authors.affiliation: Aksaray University, Aksaray Vocational School of Technical Sciences,68100 Aksaray, Turkey.
authors.forename: Meltem
authors.initials: M
authors.lastname: Alper
authors.affiliation: Balikesir University, Faculty of Science and Literature, Department of Biology, Balikesir, Turkey.
authors.forename: A Tuğşen
authors.initials: AT
authors.lastname: Aydemir
authors.affiliation: Balikesir University, Faculty of Science and Literature, Department of Biology, Balikesir, Turkey. Electronic address: feraykockar@hotmail.com.
authors.forename: Feray
authors.initials: F
authors.lastname: Köçkar
mesh_terms: D051722:ADAM Proteins / Q000235:genetics* / Q000378:metabolism; D000071096:ADAMTS Proteins; D000071121:ADAMTS4 Protein; D045744:Cell Line, Tumor; D004790:Enzyme Induction; D006801:Humans; D053582:Interleukin-1alpha / Q000502:physiology*; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System; D010006:Osteoblasts / Q000201:enzymology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011348:Procollagen N-Endopeptidase / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D015533:Transcriptional Activation
chemical_list: D053582:Interleukin-1alpha; D019869:Phosphatidylinositol 3-Kinases; D020930:MAP Kinase Kinase Kinases; D051722:ADAM Proteins; D000071096:ADAMTS Proteins; C434951:ADAMTS3 protein, human; C000609307:ADAMTS2 protein, human; D011348:Procollagen N-Endopeptidase; D000071121:ADAMTS4 Protein
keywords: ADAMTS-2; ADAMTS-3; IL-1α; MEK/JNK/PI3K; MG-63; Saos-2