title: Regulation of human chondrocyte function through direct inhibition of cartilage master regulator SOX9 by microRNA-145 (miRNA-145).
abstract: Articular cartilage enables weight bearing and near friction-free movement in the joints. Critical to its function is the production of a specialized, mechanocompetent extracellular matrix controlled by master regulator transcription factor SOX9. Mutations in SOX9 cause campomelic dysplasia, a haploinsufficiency disorder resulting in severe skeletal defects and dwarfism. Although much is understood about how SOX9 regulates cartilage matrix synthesis and hence joint function, how this master regulator is itself regulated remains largely unknown. Here we identify a specific microRNA, miR-145, as a direct regulator of SOX9 in normal healthy human articular chondrocytes. We show that miR-145 directly represses SOX9 expression in human cells through a unique binding site in its 3'-UTR not conserved in mice. Modulation of miR-145 induced profound changes in the human chondrocyte phenotype. Specifically, increased miR-145 levels cause greatly reduced expression of critical cartilage extracellular matrix genes (COL2A1 and aggrecan) and tissue-specific microRNAs (miR-675 and miR-140) and increased levels of the hypertrophic markers RUNX2 and MMP13, characteristic of changes occurring in osteoarthritis. We propose miR-145 as an important regulator of human chondrocyte function and a new target for cartilage repair.
authors.affiliation: Kennedy Institute of Rheumatology, University of Oxford, 65 Aspenlea Road, London W6 8LH, United Kingdom.
authors.forename: Aida
authors.initials: A
authors.lastname: Martinez-Sanchez
authors.forename: Katarzyna A
authors.initials: KA
authors.lastname: Dudek
authors.forename: Chris L
authors.initials: CL
authors.lastname: Murphy
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D053674:Aggrecans / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D055036:Campomelic Dysplasia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002358:Cartilage, Articular / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D019902:Chondrocytes / Q000378:metabolism* / Q000473:pathology; D024043:Collagen Type II / Q000096:biosynthesis / Q000235:genetics; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D055758:SOX9 Transcription Factor / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D020413:3' Untranslated Regions; D053674:Aggrecans; C499177:COL2A1 protein, human; D024043:Collagen Type II; C541010:MIRN145 microRNA, human; C548379:MIRN675 microRNA, human; C574758:MIRN675 microRNA, mouse; D035683:MicroRNAs; D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human
references.citation: Nat Cell Biol. 2010 Oct;12(10):1014-20
references.pmid: 20818387
references.citation: J Biol Chem. 2010 Aug 6;285(32):24381-7
references.pmid: 20529846
references.citation: Cell. 2009 May 15;137(4):647-58
references.pmid: 19409607
references.citation: Cell Death Differ. 2009 Dec;16(12):1590-8
references.pmid: 19816508
references.citation: Exp Cell Res. 2009 Aug 1;315(13):2231-40
references.pmid: 19306868
references.citation: Dev Dyn. 1997 Aug;209(4):377-86
references.pmid: 9264261
references.citation: Osteoarthritis Cartilage. 2004 Dec;12(12):963-73
references.pmid: 15564063
references.citation: Nat Commun. 2011;2:251
references.pmid: 21427722
references.citation: Pathobiology. 2008;75(3):195-9
references.pmid: 18550917
references.citation: Biochem Biophys Res Commun. 2003 Feb 7;301(2):338-43
references.pmid: 12565865
references.citation: Arthritis Res Ther. 2007;9(5):R107
references.pmid: 17935617
references.citation: Cell. 2007 Dec 28;131(7):1273-86
references.pmid: 18155131
references.citation: Mol Cell Biol. 2008 Aug;28(16):4999-5013
references.pmid: 18559420
references.citation: Osteoarthritis Cartilage. 2006 Jun;14(6):561-70
references.pmid: 16735197
references.citation: Nat Genet. 1999 May;22(1):85-9
references.pmid: 10319868
references.citation: J Clin Invest. 1997 Apr 1;99(7):1534-45
references.pmid: 9119997
references.citation: Development. 2005 Nov;132(21):4653-62
references.pmid: 16224045
references.citation: Genes Dev. 2009 Sep 15;23(18):2166-78
references.pmid: 19720868
references.citation: Arthritis Rheum. 2007 Jan;56(1):158-67
references.pmid: 17195218
references.citation: Genes Dev. 2002 Nov 1;16(21):2813-28
references.pmid: 12414734
references.citation: Circ Res. 2010 Mar 5;106(4):712-9
references.pmid: 20056916
references.citation: Arthritis Rheum. 2009 Sep;60(9):2723-30
references.pmid: 19714579
references.citation: Mol Cell Biol. 1997 Apr;17(4):2336-46
references.pmid: 9121483
references.citation: Nat Genet. 1997 Jun;16(2):174-8
references.pmid: 9171829
references.citation: Genes Dev. 2010 Jun 1;24(11):1173-85
references.pmid: 20466812
references.citation: Curr Opin Cell Biol. 2009 Jun;21(3):452-60
references.pmid: 19450959
references.citation: J Cell Physiol. 2004 Jun;199(3):451-9
references.pmid: 15095292
references.citation: Science. 2007 Apr 27;316(5824):575-9
references.pmid: 17379774
references.citation: J Biol Chem. 2000 Apr 14;275(15):10738-44
references.pmid: 10753864
references.citation: Osteoarthritis Cartilage. 2009 Apr;17(4):464-72
references.pmid: 19008124
references.citation: PLoS One. 2011;6(7):e21679
references.pmid: 21799743
references.citation: Development. 2010 Mar;137(6):901-11
references.pmid: 20179096
references.citation: Nature. 1994 Dec 8;372(6506):525-30
references.pmid: 7990924
references.citation: Arthritis Rheum. 2007 Oct;56(10):3297-306
references.pmid: 17907154