title: The circadian clock in murine chondrocytes regulates genes controlling key aspects of cartilage homeostasis.
abstract: OBJECTIVE
  To characterize the circadian clock in murine cartilage tissue and identify tissue-specific clock target genes, and to investigate whether the circadian clock changes during aging or during cartilage degeneration using an experimental mouse model of osteoarthritis (OA).
  
  
  METHODS
  Cartilage explants were obtained from aged and young adult mice after transduction with the circadian clock fusion protein reporter PER2::luc, and real-time bioluminescence recordings were used to characterize the properties of the clock. Time-series microarrays were performed on mouse cartilage tissue to identify genes expressed in a circadian manner. Rhythmic genes were confirmed by quantitative reverse transcription-polymerase chain reaction using mouse tissue, primary chondrocytes, and a human chondrocyte cell line. Experimental OA was induced in mice by destabilization of the medial meniscus (DMM), and articular cartilage samples were microdissected and subjected to microarray analysis.
  
  
  RESULTS
  Mouse cartilage tissue and a human chondrocyte cell line were found to contain intrinsic molecular circadian clocks. The cartilage clock could be reset by temperature signals, while the circadian period was temperature compensated. PER2::luc bioluminescence demonstrated that circadian oscillations were significantly lower in amplitude in cartilage from aged mice. Time-series microarray analyses of the mouse tissue identified the first circadian transcriptome in cartilage, revealing that 615 genes (∼3.9% of the expressed genes) displayed a circadian pattern of expression. This included genes involved in cartilage homeostasis and survival, as well as genes with potential importance in the pathogenesis of OA. Several clock genes were disrupted in the early stages of cartilage degeneration in the DMM mouse model of OA.
  
  
  CONCLUSIONS
  These results reveal an autonomous circadian clock in chondrocytes that can be implicated in key aspects of cartilage biology and pathology. Consequently, circadian disruption (e.g., during aging) may compromise tissue homeostasis and increase susceptibility to joint damage or disease.
authors.affiliation: University of Manchester, Manchester, UK.
authors.forename: Nicole
authors.initials: N
authors.lastname: Gossan
authors.forename: Leo
authors.initials: L
authors.lastname: Zeef
authors.forename: James
authors.initials: J
authors.lastname: Hensman
authors.forename: Alun
authors.initials: A
authors.lastname: Hughes
authors.forename: John F
authors.initials: JF
authors.lastname: Bateman
authors.forename: Lynn
authors.initials: L
authors.lastname: Rowley
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Little
authors.forename: Hugh D
authors.initials: HD
authors.lastname: Piggins
authors.forename: Magnus
authors.initials: M
authors.lastname: Rattray
authors.forename: Raymond P
authors.initials: RP
authors.lastname: Boot-Handford
authors.forename: Qing-Jun
authors.initials: QJ
authors.lastname: Meng
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics / Q000378:metabolism; D002358:Cartilage, Articular / Q000378:metabolism*; D002460:Cell Line; D019902:Chondrocytes / Q000378:metabolism*; D057906:Circadian Clocks / Q000502:physiology*; D005786:Gene Expression Regulation; D006706:Homeostasis / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D010003:Osteoarthritis / Q000235:genetics / Q000378:metabolism; D056950:Period Circadian Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C513312:Per2 protein, mouse; D056950:Period Circadian Proteins
references.citation: PLoS Biol. 2007 Feb;5(2):e34
references.pmid: 17298173
references.citation: Nature. 2012 Mar 29;485(7396):62-8
references.pmid: 22460951
references.citation: J Biol Chem. 2012 Oct 19;287(43):36081-95
references.pmid: 22936800
references.citation: Gerontology. 2011;57(5):427-34
references.pmid: 20980722
references.citation: Proc Natl Acad Sci U S A. 2011 Apr 26;108(17):7218-23
references.pmid: 21482780
references.citation: Best Pract Res Clin Rheumatol. 2006 Oct;20(5):983-1002
references.pmid: 16980219
references.citation: Curr Biol. 2010 Mar 23;20(6):533-7
references.pmid: 20226667
references.citation: PLoS Biol. 2011 Feb;9(2):e1000595
references.pmid: 21364973
references.citation: J Physiol Paris. 2006 Nov-Dec;100(5-6):252-60
references.pmid: 17629684
references.citation: Proc Natl Acad Sci U S A. 2004 Apr 13;101(15):5339-46
references.pmid: 14963227
references.citation: Nat Protoc. 2008;3(8):1253-60
references.pmid: 18714293
references.citation: Proc Soc Exp Biol Med. 1984 Sep;176(4):342-5
references.pmid: 6463044
references.citation: Arthritis Res Ther. 2012 May 23;14(3):R122
references.pmid: 22621205
references.citation: PLoS One. 2011 Jan 11;6(1):e15848
references.pmid: 21264318
references.citation: Clin Exp Rheumatol. 2008 Jan-Feb;26(1):139-45
references.pmid: 18328163
references.citation: PLoS Comput Biol. 2012;8(7):e1002585
references.pmid: 22807663
references.citation: Nat Rev Genet. 2008 Oct;9(10):764-75
references.pmid: 18802415
references.citation: Science. 2012 Oct 19;338(6105):379-83
references.pmid: 22923437
references.citation: PLoS Genet. 2012;8(7):e1002835
references.pmid: 22844252
references.citation: Genesis. 2005 Mar;41(3):122-32
references.pmid: 15739187
references.citation: Br Med Bull. 2008;87:77-95
references.pmid: 18676397
references.citation: Prog Brain Res. 2012;199:305-336
references.pmid: 22877673
references.citation: Science. 2010 Oct 15;330(6002):379-85
references.pmid: 20947768
references.citation: Bioinformatics. 2008 Jun 15;24(12):1461-2
references.pmid: 18441000
references.citation: Physiol Genomics. 2007 Sep 19;31(1):86-95
references.pmid: 17550994
references.citation: Ann Rheum Dis. 2002 Dec;61(12):1075-80
references.pmid: 12429538
references.citation: Science. 2012 Aug 31;337(6098):1094-7
references.pmid: 22798407
references.citation: Osteoarthritis Cartilage. 2005 Aug;13(8):697-708
references.pmid: 15950496
references.citation: J Immunol. 2010 Feb 1;184(3):1560-5
references.pmid: 20042581
references.citation: Lancet. 2012 Sep 1;380(9844):815-23
references.pmid: 22763110
references.citation: Nat Rev Neurosci. 2003 Aug;4(8):649-61
references.pmid: 12894240
references.citation: Arthritis Res Ther. 2006;8(4):R124
references.pmid: 16859525
references.citation: Nature. 2002 Aug 29;418(6901):935-41
references.pmid: 12198538
references.citation: J Orthop Res. 1990 Jan;8(1):132-5
references.pmid: 2293628
references.citation: PLoS One. 2010 Jul 12;5(7):e11527
references.pmid: 20634945
references.citation: Cell. 2002 May 3;109(3):307-20
references.pmid: 12015981
references.citation: Curr Drug Targets. 2010 May;11(5):614-9
references.pmid: 20199389
references.citation: PLoS Genet. 2009 Apr;5(4):e1000442
references.pmid: 19343201
references.citation: J Biol Rhythms. 2010 Oct;25(5):372-80
references.pmid: 20876817
references.citation: Ann Rheum Dis. 1991 Apr;50(4):243-8
references.pmid: 2029206
references.citation: Science. 1994 Apr 29;264(5159):719-25
references.pmid: 8171325
references.citation: Mod Rheumatol. 2006;16(3):131-6
references.pmid: 16767550
references.citation: Arthritis Rheum. 2013 Jun;65(6):1547-60
references.pmid: 23436205
references.citation: Annu Rev Pharmacol Toxicol. 2007;47:593-628
references.pmid: 17209800
references.citation: Arthritis Res Ther. 2009;11(3):R96
references.pmid: 19549314