title: Mechanosensor polycystin-1 potentiates differentiation of human osteoblastic cells by upregulating Runx2 expression via induction of JAK2/STAT3 signaling axis.
abstract: Polycystin-1 (PC1) has been proposed as a chief mechanosensing molecule implicated in skeletogenesis and bone remodeling. Mechanotransduction via PC1 involves proteolytic cleavage of its cytoplasmic tail (CT) and interaction with intracellular pathways and transcription factors to regulate cell function. Here we demonstrate the interaction of PC1-CT with JAK2/STAT3 signaling axis in mechanically stimulated human osteoblastic cells, leading to transcriptional induction of Runx2 gene, a master regulator of osteoblastic differentiation. Primary osteoblast-like PC1-expressing cells subjected to mechanical-stretching exhibited a PC1-dependent increase of the phosphorylated(p)/active form of JAK2. Specific interaction of PC1-CT with pJAK2 was observed after stretching while pre-treatment of cells with PC1 (anti-IgPKD1) and JAK2 inhibitors abolished JAK2 activation. Consistently, mechanostimulation triggered PC1-mediated phosphorylation and nuclear translocation of STAT3. The nuclear phosphorylated(p)/DNA-binding competent pSTAT3 levels were augmented after stretching followed by elevated DNA-binding activity. Pre-treatment with a STAT3 inhibitor either alone or in combination with anti-IgPKD1 abrogated this effect. Moreover, PC1-mediated mechanostimulation induced elevation of Runx2 mRNA levels. ChIP assays revealed direct regulation of Runx2 promoter activity by STAT3/Runx2 after mechanical-stretching that was PC1-dependent. Our findings show that mechanical load upregulates expression of Runx2 gene via potentiation of PC1-JAK2/STAT3 signaling axis, culminating to possibly control osteoblastic differentiation and ultimately bone formation.
authors.affiliation: Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 75, M. Asias Street, 11527, Athens, Greece.
authors.forename: Georgia
authors.initials: G
authors.lastname: Dalagiorgou
authors.affiliation: Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 75, M. Asias Street, 11527, Athens, Greece.
authors.forename: Christina
authors.initials: C
authors.lastname: Piperi
authors.affiliation: Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 75, M. Asias Street, 11527, Athens, Greece.
authors.forename: Christos
authors.initials: C
authors.lastname: Adamopoulos
authors.affiliation: Molecular Virology Laboratory, Hellenic Pasteur Institute, 11521, Athens, Greece.
authors.forename: Urania
authors.initials: U
authors.lastname: Georgopoulou
authors.affiliation: Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 75, M. Asias Street, 11527, Athens, Greece.
authors.forename: Antonios N
authors.initials: AN
authors.lastname: Gargalionis
authors.affiliation: Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 75, M. Asias Street, 11527, Athens, Greece.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Spyropoulou
authors.affiliation: Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 75, M. Asias Street, 11527, Athens, Greece.
authors.forename: Ilianna
authors.initials: I
authors.lastname: Zoi
authors.affiliation: Section of Experimental Dento-Maxillo-Facial Medicine, Center of Dento-Maxillo-Facial Medicine, University of Bonn, 53111, Bonn, Germany.
authors.forename: Marjan
authors.initials: M
authors.lastname: Nokhbehsaim
authors.affiliation: Section of Experimental Dento-Maxillo-Facial Medicine, Center of Dento-Maxillo-Facial Medicine, University of Bonn, 53111, Bonn, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Damanaki
authors.affiliation: Section of Experimental Dento-Maxillo-Facial Medicine, Center of Dento-Maxillo-Facial Medicine, University of Bonn, 53111, Bonn, Germany.
authors.forename: James
authors.initials: J
authors.lastname: Deschner
authors.affiliation: Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 75, M. Asias Street, 11527, Athens, Greece. ebasdra@med.uoa.gr.
authors.forename: Efthimia K
authors.initials: EK
authors.lastname: Basdra
authors.affiliation: Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 75, M. Asias Street, 11527, Athens, Greece. papavas@med.uoa.gr.
authors.forename: Athanasios G
authors.initials: AG
authors.lastname: Papavassiliou
mesh_terms: D001483:Base Sequence; D002454:Cell Differentiation; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics* / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D006801:Humans; D053614:Janus Kinase 2 / Q000378:metabolism*; D040542:Mechanotransduction, Cellular; D008954:Models, Biological; D010006:Osteoblasts / Q000166:cytology* / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D021381:Protein Transport; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D050396:TRPP Cation Channels / Q000737:chemistry / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics*
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; D004247:DNA; D053614:Janus Kinase 2; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; D050396:TRPP Cation Channels; C507924:JAK2 protein, human
keywords: Gene regulation; JAK/STAT pathway; Mechanosensor; Mechanotransduction; Osteoblastic differentiation; Polycystin-1; Runx2