title: MicroRNA-140 plays dual roles in both cartilage development and homeostasis.
abstract: Osteoarthritis (OA), the most prevalent aging-related joint disease, is characterized by insufficient extracellular matrix synthesis and articular cartilage degradation, mediated by several proteinases, including Adamts-5. miR-140 is one of a very limited number of noncoding microRNAs (miRNAs) specifically expressed in cartilage; however, its role in development and/or tissue maintenance is largely uncharacterized. To examine miR-140 function in tissue development and homeostasis, we generated a mouse line through a targeted deletion of miR-140. miR-140(-/-) mice manifested a mild skeletal phenotype with a short stature, although the structure of the articular joint cartilage appeared grossly normal in 1-mo-old miR-140(-/-) mice. Interestingly, miR-140(-/-) mice showed age-related OA-like changes characterized by proteoglycan loss and fibrillation of articular cartilage. Conversely, transgenic (TG) mice overexpressing miR-140 in cartilage were resistant to antigen-induced arthritis. OA-like changes in miR-140-deficient mice can be attributed, in part, to elevated Adamts-5 expression, regulated directly by miR-140. We show that miR-140 regulates cartilage development and homeostasis, and its loss contributes to the development of age-related OA-like changes.
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Miyaki
authors.forename: Tempei
authors.initials: T
authors.lastname: Sato
authors.forename: Atsushi
authors.initials: A
authors.lastname: Inoue
authors.forename: Shuhei
authors.initials: S
authors.lastname: Otsuki
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Ito
authors.forename: Shigetoshi
authors.initials: S
authors.lastname: Yokoyama
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Kato
authors.forename: Fuko
authors.initials: F
authors.lastname: Takemoto
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Nakasa
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yamashita
authors.forename: Shuji
authors.initials: S
authors.lastname: Takada
authors.forename: Martin K
authors.initials: MK
authors.lastname: Lotz
authors.forename: Hiroe
authors.initials: H
authors.lastname: Ueno-Kudo
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Asahara
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism; D000071116:ADAMTS5 Protein; D000818:Animals; D001846:Bone Development / Q000235:genetics; D002356:Cartilage / Q000254:growth & development*; D006706:Homeostasis / Q000235:genetics / Q000502:physiology*; D007719:Knee Joint / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D010003:Osteoarthritis / Q000473:pathology
chemical_list: C547828:MIRN140 microRNA, mouse; D035683:MicroRNAs; D051722:ADAM Proteins; D000071116:ADAMTS5 Protein; C498489:Adamts5 protein, mouse
references.citation: Cell. 2009 Jan 9;136(1):26-36
references.pmid: 19135886
references.citation: J Cell Sci. 1995 Dec;108 ( Pt 12):3677-84
references.pmid: 8719874
references.citation: Genes Dev. 2008 Dec 1;22(23):3242-54
references.pmid: 19015276
references.citation: Arthritis Res Ther. 2009;11(3):224
references.pmid: 19519926
references.citation: Science. 2007 Apr 27;316(5824):575-9
references.pmid: 17379774
references.citation: Cell. 2005 Jan 14;120(1):15-20
references.pmid: 15652477
references.citation: Osteoarthritis Cartilage. 2007 Sep;15(9):1061-9
references.pmid: 17470400
references.citation: Nature. 2005 Mar 31;434(7033):648-52
references.pmid: 15800625
references.citation: J Cell Biol. 2001 Apr 2;153(1):87-100
references.pmid: 11285276
references.citation: Arthritis Rheum. 2004 Aug;50(8):2547-58
references.pmid: 15334469
references.citation: Science. 2005 Jul 8;309(5732):310-1
references.pmid: 15919954
references.citation: PLoS One. 2008;3(11):e3740
references.pmid: 19011694
references.citation: Nature. 2005 Feb 17;433(7027):769-73
references.pmid: 15685193
references.citation: FEBS Lett. 2006 Jul 24;580(17):4214-7
references.pmid: 16828749
references.citation: Proc Natl Acad Sci U S A. 2008 Feb 12;105(6):1949-54
references.pmid: 18238902
references.citation: Cell. 2004 Nov 12;119(4):555-66
references.pmid: 15537544
references.citation: Cell. 2007 Apr 20;129(2):303-17
references.pmid: 17397913
references.citation: Mod Rheumatol. 2008;18(3):213-9
references.pmid: 18351289
references.citation: Arthritis Rheum. 2003 Oct;48(10):2873-80
references.pmid: 14558093
references.citation: Proc Natl Acad Sci U S A. 2006 Nov 28;103(48):18255-60
references.pmid: 17108080
references.citation: J Cell Physiol. 2007 Dec;213(3):626-34
references.pmid: 17786965
references.citation: Nat Rev Mol Cell Biol. 2008 Mar;9(3):219-30
references.pmid: 18270516
references.citation: Med Res Rev. 2008 May;28(3):464-81
references.pmid: 17880012
references.citation: Cell Death Differ. 2009 Dec;16(12):1590-8
references.pmid: 19816508
references.citation: J Biol Chem. 1996 Feb 23;271(8):4298-303
references.pmid: 8626777
references.citation: Orthop Clin North Am. 1971 Mar;2(1):19-31
references.pmid: 4940528
references.citation: Arthritis Rheum. 2008 May;58(5):1284-92
references.pmid: 18438844
references.citation: Proc Natl Acad Sci U S A. 2005 Aug 2;102(31):10898-903
references.pmid: 16040801
references.citation: Genes Dev. 2006 Mar 1;20(5):515-24
references.pmid: 16510870
references.citation: Arthritis Rheum. 2009 Sep;60(9):2723-30
references.pmid: 19714579
references.citation: Arthritis Rheum. 2009 Apr;60(4):1035-41
references.pmid: 19333945
references.citation: Dev Cell. 2009 Dec;17(6):836-48
references.pmid: 20059953
references.citation: J Biol Chem. 2002 Jun 21;277(25):22201-8
references.pmid: 11956193
references.citation: Nat Med. 2009 Dec;15(12):1421-5
references.pmid: 19915594
references.citation: Cell. 2004 Jan 23;116(2):281-97
references.pmid: 14744438
references.citation: Matrix Biol. 2000 Sep;19(5):389-94
references.pmid: 10980415
references.citation: Nature. 2005 Mar 31;434(7033):644-8
references.pmid: 15800624
references.citation: Arthritis Rheum. 2001 Jun;44(6):1455-65
references.pmid: 11407708
references.citation: Mol Biol Rep. 2007 Dec;34(4):225-31
references.pmid: 17211519
references.citation: Arthritis Rheum. 2008 Apr;58(4):1001-9
references.pmid: 18383392