title: Oncostatin M is a novel inhibitor of TGF-β1-induced matricellular protein expression.
abstract: Matricellular proteins in the kidney have been associated with the development of tubulointerstitial fibrogenesis and the progression of renal disease. This study investigated potential antifibrotic effects of the cytokine oncostatin M (OSM) in human proximal tubule cells (PTC), particularly with regard to inhibition of profibrotic events initiated by TGF-β1. In human PTC, OSM diminished transforming growth factor (TGF)-β1-induced expression of the transcriptional epithelial-mesenchymal transition mediator FoxC2. Furthermore, exposure to OSM attenuated basal and TGF-β1-induced expression of the matricellular proteins SPARC, TSP-1, TNC, and CTGF regardless of the sequence of ligand administration. OSM was shown to result in rapid and sustained phosphorylation of both Stat1 and Stat3 and also in transient phosphorylation of Smad2/3 in contrast to TGF-β1, which demonstrated a gradually building phosphorylation of Smad2/3 and a brief phosphorylation of Smad1/5/8. Utilizing receptor-blocking molecules, we found the inhibitory effect of OSM on TGF-β1-induced CTGF mRNA expression occurs independently of Smad2/3 signaling and present evidence that this effect may be partially driven by OSM receptor-mediated Stat1 and/or Stat3 signaling pathways, thereby providing a mechanism whereby OSM can contribute to tubulointerstitial protection.
authors.affiliation: Department of Internal Medicine IV, Nephrology and Hypertension, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Rita
authors.initials: R
authors.lastname: Sarközi
authors.forename: Christine
authors.initials: C
authors.lastname: Hauser
authors.forename: Susie-Jane
authors.initials: SJ
authors.lastname: Noppert
authors.forename: Andreas
authors.initials: A
authors.lastname: Kronbichler
authors.forename: Markus
authors.initials: M
authors.lastname: Pirklbauer
authors.forename: Viktoria Maria
authors.initials: VM
authors.lastname: Haller
authors.forename: Johannes
authors.initials: J
authors.lastname: Grillari
authors.forename: Regina
authors.initials: R
authors.lastname: Grillari-Voglauer
authors.forename: Gert
authors.initials: G
authors.lastname: Mayer
authors.forename: Herbert
authors.initials: H
authors.lastname: Schramek
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D002460:Cell Line; D055513:Connective Tissue Growth Factor / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis*; D005355:Fibrosis / Q000517:prevention & control; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008024:Ligands; D053683:Oncostatin M / Q000494:pharmacology*; D015676:Osteonectin / Q000378:metabolism; D010766:Phosphorylation; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D060888:Real-Time Polymerase Chain Reaction; D053677:Receptors, Oncostatin M / Q000037:antagonists & inhibitors; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050795:STAT2 Transcription Factor / Q000378:metabolism; D051785:Smad Proteins / Q000378:metabolism; D019063:Tenascin / Q000378:metabolism; D019700:Thrombospondin 1 / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D016326:Extracellular Matrix Proteins; D051858:Forkhead Transcription Factors; D008024:Ligands; D015676:Osteonectin; D053677:Receptors, Oncostatin M; C468135:SMOC1 protein, human; D050794:STAT1 Transcription Factor; D050795:STAT2 Transcription Factor; D051785:Smad Proteins; D019063:Tenascin; D019700:Thrombospondin 1; D053773:Transforming Growth Factor beta1; C082078:mesenchyme fork head 1 protein; D053683:Oncostatin M; D055513:Connective Tissue Growth Factor; D012313:RNA