MicroRNA-140 plays dual roles in both cartilage development and homeostasis.
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.
Miyaki
Shigeru
S
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, USA.
Sato
Tempei
T
Inoue
Atsushi
A
Otsuki
Shuhei
S
Ito
Yoshiaki
Y
Yokoyama
Shigetoshi
S
Kato
Yoshio
Y
Takemoto
Fuko
F
Nakasa
Tomoyuki
T
Yamashita
Satoshi
S
Takada
Shuji
S
Lotz
Martin K
MK
Ueno-Kudo
Hiroe
H
Asahara
Hiroshi
H
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
C547828:MIRN140 microRNA, mouse; D035683:MicroRNAs; D051722:ADAM Proteins; D000071116:ADAMTS5 Protein; C498489:Adamts5 protein, mouse
Cell. 2009 Jan 9;136(1):26-36
19135886
J Cell Sci. 1995 Dec;108 ( Pt 12):3677-84
8719874
Genes Dev. 2008 Dec 1;22(23):3242-54
19015276
Arthritis Res Ther. 2009;11(3):224
19519926
Science. 2007 Apr 27;316(5824):575-9
17379774
Cell. 2005 Jan 14;120(1):15-20
15652477
Osteoarthritis Cartilage. 2007 Sep;15(9):1061-9
17470400
Nature. 2005 Mar 31;434(7033):648-52
15800625
J Cell Biol. 2001 Apr 2;153(1):87-100
11285276
Arthritis Rheum. 2004 Aug;50(8):2547-58
15334469
Science. 2005 Jul 8;309(5732):310-1
15919954
PLoS One. 2008;3(11):e3740
19011694
Nature. 2005 Feb 17;433(7027):769-73
15685193
FEBS Lett. 2006 Jul 24;580(17):4214-7
16828749
Proc Natl Acad Sci U S A. 2008 Feb 12;105(6):1949-54
18238902
Cell. 2004 Nov 12;119(4):555-66
15537544
Cell. 2007 Apr 20;129(2):303-17
17397913
Mod Rheumatol. 2008;18(3):213-9
18351289
Arthritis Rheum. 2003 Oct;48(10):2873-80
14558093
Proc Natl Acad Sci U S A. 2006 Nov 28;103(48):18255-60
17108080
J Cell Physiol. 2007 Dec;213(3):626-34
17786965
Nat Rev Mol Cell Biol. 2008 Mar;9(3):219-30
18270516
Med Res Rev. 2008 May;28(3):464-81
17880012
Cell Death Differ. 2009 Dec;16(12):1590-8
19816508
J Biol Chem. 1996 Feb 23;271(8):4298-303
8626777
Orthop Clin North Am. 1971 Mar;2(1):19-31
4940528
Arthritis Rheum. 2008 May;58(5):1284-92
18438844
Proc Natl Acad Sci U S A. 2005 Aug 2;102(31):10898-903
16040801
Genes Dev. 2006 Mar 1;20(5):515-24
16510870
Arthritis Rheum. 2009 Sep;60(9):2723-30
19714579
Arthritis Rheum. 2009 Apr;60(4):1035-41
19333945
Dev Cell. 2009 Dec;17(6):836-48
20059953
J Biol Chem. 2002 Jun 21;277(25):22201-8
11956193
Nat Med. 2009 Dec;15(12):1421-5
19915594
Cell. 2004 Jan 23;116(2):281-97
14744438
Matrix Biol. 2000 Sep;19(5):389-94
10980415
Nature. 2005 Mar 31;434(7033):644-8
15800624
Arthritis Rheum. 2001 Jun;44(6):1455-65
11407708
Mol Biol Rep. 2007 Dec;34(4):225-31
17211519
Arthritis Rheum. 2008 Apr;58(4):1001-9
18383392