title: miR-23a-3p causes cellular senescence by targeting hyaluronan synthase 2: possible implication for skin aging.
abstract: Even though aging and cellular senescence appear to be linked, the biological mechanisms interconnecting these two processes remain to be unravelled. Therefore, microRNA (miRNA/miR) profiles were analyzed ex vivo by means of gene array in fibroblasts isolated from young and old human donors. Expression of several miRNAs was positively correlated with donor age. Among them, miR-23a-3p was shown to target hyaluronan synthase 2 (HAS2). HA is a polysaccharide of the extracellular matrix that critically regulates the phenotype of fibroblasts. Indeed, both aged and senescent fibroblasts showed increased miR-23a-3p expression and secreted significantly lower amounts of HA compared with young and non-senescent fibroblasts. Ectopic overexpression of miR-23a-3p in non-senescent fibroblasts led to decreased HAS2-mediated HA synthesis, upregulation of senescence-associated markers, and decreased proliferation. In addition, siRNA-mediated downregulation of HAS2 and pharmacological inhibition of HA synthesis by 4-methylumbelliferone mimicked the effects of miR-23a-3p. In vivo, miR-23a-3p was upregulated and HAS2 was downregulated in the skin of old mice compared with young mice. Inhibition of HA synthesis by 4-methylumbelliferone in mice reduced dermal hydration and viscoelasticity, thereby mimicking an aged skin phenotype. Taken together, these findings appear to link miR-23a-3p and the HA microenvironment as effector mechanisms in both dermal aging and senescence.
authors.affiliation: Institut für Pharmakologie und Klinische Pharmakologie, Universitätsklinikum der Heinrich-Heine-Universität, Düsseldorf, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Röck
authors.affiliation: Institut für Umweltmedizinische Forschung (IUF), Düsseldorf, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Tigges
authors.affiliation: Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), Neuherberg, Germany; Department of Mathematics, Technische Universität München, Garching, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Sass
authors.affiliation: Institut für Pharmakologie und Klinische Pharmakologie, Universitätsklinikum der Heinrich-Heine-Universität, Düsseldorf, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Schütze
authors.affiliation: Institut für Neuropathologie, Universitätsklinikum der Heinrich-Heine-Universität, Düsseldorf, Germany.
authors.forename: Ana-Maria
authors.initials: AM
authors.lastname: Florea
authors.affiliation: Institut für Pharmakologie und Klinische Pharmakologie, Universitätsklinikum der Heinrich-Heine-Universität, Düsseldorf, Germany.
authors.forename: Anke C
authors.initials: AC
authors.lastname: Fender
authors.affiliation: Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), Neuherberg, Germany; Department of Mathematics, Technische Universität München, Garching, Germany.
authors.forename: Florian J
authors.initials: FJ
authors.lastname: Theis
authors.affiliation: Institut für Umweltmedizinische Forschung (IUF), Düsseldorf, Germany.
authors.forename: Jean
authors.initials: J
authors.lastname: Krutmann
authors.affiliation: Institute for Clinical Chemistry and Laboratory Diagnostics, Heinrich Heine University, Düsseldorf, Germany.
authors.forename: Fritz
authors.initials: F
authors.lastname: Boege
authors.affiliation: Institut für Umweltmedizinische Forschung (IUF), Düsseldorf, Germany.
authors.forename: Ellen
authors.initials: E
authors.lastname: Fritsche
authors.affiliation: Institut für Neuropathologie, Universitätsklinikum der Heinrich-Heine-Universität, Düsseldorf, Germany.
authors.forename: Guido
authors.initials: G
authors.lastname: Reifenberger
authors.affiliation: Institut für Pharmakologie und Klinische Pharmakologie, Universitätsklinikum der Heinrich-Heine-Universität, Düsseldorf, Germany. Electronic address: jens.fischer@uni-duesseldorf.de.
authors.forename: Jens W
authors.initials: JW
authors.lastname: Fischer
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000328:Adult; D000368:Aged; D000818:Animals; D016922:Cellular Senescence; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000502:physiology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors / Q000235:genetics*; D006801:Humans; D000076002:Hyaluronan Synthases; D006820:Hyaluronic Acid / Q000378:metabolism; D006923:Hymecromone / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000502:physiology*; D008875:Middle Aged; D015595:Skin Aging
chemical_list: D020413:3' Untranslated Regions; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C552430:MIRN23a microRNA, human; D035683:MicroRNAs; C534062:Mirn23b microRNA, mouse; D006923:Hymecromone; D006820:Hyaluronic Acid; D014453:Glucuronosyltransferase; C101754:HAS2 protein, human; C491099:Has2 protein, mouse; D000076002:Hyaluronan Synthases