title: Environmental disruption of circadian rhythm predisposes mice to osteoarthritis-like changes in knee joint.
abstract: Circadian rhythm dysfunction is linked to many diseases, yet pathophysiological roles in articular cartilage homeostasis and degenerative joint disease including osteoarthritis (OA) remains to be investigated in vivo. Here, we tested whether environmental or genetic disruption of circadian homeostasis predisposes to OA-like pathological changes. Male mice were examined for circadian locomotor activity upon changes in the light:dark (LD) cycle or genetic disruption of circadian rhythms. Wild-type (WT) mice were maintained on a constant 12 h:12 h LD cycle (12:12 LD) or exposed to weekly 12 h phase shifts. Alternatively, male circadian mutant mice (Clock(Δ19) or Csnk1e(tau) mutants) were compared with age-matched WT littermates that were maintained on a constant 12:12 LD cycle. Disruption of circadian rhythms promoted osteoarthritic changes by suppressing proteoglycan accumulation, upregulating matrix-degrading enzymes and downregulating anabolic mediators in the mouse knee joint. Mechanistically, these effects involved activation of the PKCδ-ERK-RUNX2/NFκB and β-catenin signaling pathways, stimulation of MMP-13 and ADAMTS-5, as well as suppression of the anabolic mediators SOX9 and TIMP-3 in articular chondrocytes of phase-shifted mice. Genetic disruption of circadian homeostasis does not predispose to OA-like pathological changes in joints. Our results, for the first time, provide compelling in vivo evidence that environmental disruption of circadian rhythms is a risk factor for the development of OA-like pathological changes in the mouse knee joint.
authors: Department of Biochemistry, Rush University Medical Center, Chicago, IL, 60612.
authors: Ranjan
authors: R
authors: Kc
authors: Department of Biochemistry, Rush University Medical Center, Chicago, IL, 60612.
authors: Xin
authors: X
authors: Li
authors: Section of Division of Digestive Diseases and Nutrition, Rush University Medical Center, Chicago, IL, 60612.
authors: Robin M
authors: RM
authors: Voigt
authors: Department of Biochemistry, Rush University Medical Center, Chicago, IL, 60612.|Department of Orthopaedic Surgery, Internal Medicine, Rush University Medical Center, Chicago, IL, 60612.
authors: Michael B
authors: MB
authors: Ellman
authors: Center for Sleep and Circadian Biology, Department of Neurobiology, Northwestern University, Evanston, IL, 60208.
authors: Keith C
authors: KC
authors: Summa
authors: Center for Sleep and Circadian Biology, Department of Neurobiology, Northwestern University, Evanston, IL, 60208.
authors: Martha Hotz
authors: MH
authors: Vitaterna
authors: Section of Division of Digestive Diseases and Nutrition, Rush University Medical Center, Chicago, IL, 60612.|Section of Pharmacology, Rush University Medical Center, Chicago, IL, 60612.|Section of Molecular Biophysics and Physiology, Rush University Medical Center, Chicago, IL, 60612.|Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Netherlands.
authors: Ali
authors: A
authors: Keshavarizian
authors: Center for Sleep and Circadian Biology, Department of Neurobiology, Northwestern University, Evanston, IL, 60208.
authors: Fred W
authors: FW
authors: Turek
authors: Qing-Jun Meng, Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom, M13 9PT.
authors: Qing-Jun
authors: QJ
authors: Meng
authors: Department of Biochemistry, Vermont Cancer Center for Basic and Translational Research, University of Vermont Medical School, Burlington, VT, USA.
authors: Gary S
authors: GS
authors: Stein
authors: Departments of Orthopedic Surgery & Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA.
authors: Andre J
authors: AJ
authors: van Wijnen
authors: Department of Biochemistry, Rush University Medical Center, Chicago, IL, 60612.
authors: Di
authors: D
authors: Chen
authors: Section of Division of Digestive Diseases and Nutrition, Rush University Medical Center, Chicago, IL, 60612.
authors: Christopher B
authors: CB
authors: Forsyth
authors: Department of Biochemistry, Rush University Medical Center, Chicago, IL, 60612.|Department of Orthopaedic Surgery, Internal Medicine, Rush University Medical Center, Chicago, IL, 60612.|Section of Rheumatology, Rush University Medical Center, Chicago, IL, 60612.|Department of Bioengineering, University of Illinois at Chicago, Chicago, IL, 60612.
authors: Hee-Jeong
authors: HJ
authors: Im
mesh_terms: D000818:Animals; D056926:CLOCK Proteins / Q000235:genetics*; D002358:Cartilage, Articular / Q000378:metabolism* / Q000473:pathology; D002940:Circadian Rhythm / Q000235:genetics* / Q000502:physiology; D050659:Core Binding Factor Alpha 1 Subunit / Q000096:biosynthesis; D004198:Disease Susceptibility; D004777:Environment; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D007719:Knee Joint / Q000378:metabolism / Q000503:physiopathology; D020935:MAP Kinase Signaling System / Q000235:genetics; D053509:Matrix Metalloproteinase 13 / Q000096:biosynthesis; D051379:Mice; D009043:Motor Activity / Q000235:genetics / Q000502:physiology; D020370:Osteoarthritis, Knee / Q000235:genetics* / Q000503:physiopathology
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; C493716:Runx2 protein, mouse; D056926:CLOCK Proteins; C538944:Clock protein, mouse; D053509:Matrix Metalloproteinase 13
references: Chem Biol. 2001 Dec;8(12):1123-9
references: 11755391
references: J Cell Biochem. 2012 Sep;113(9):2856-65
references: 22488450
references: Cell. 1997 May 16;89(4):641-53
references: 9160755
references: J Immunol. 2010 Feb 1;184(3):1560-5
references: 20042581
references: Sci Transl Med. 2012 Apr 11;4(129):129ra43
references: 22496545
references: J Biol Chem. 2012 Oct 19;287(43):36081-95
references: 22936800
references: Aging Clin Exp Res. 2003 Oct;15(5):364-72
references: 14703002
references: N Engl J Med. 2012 Jul 12;367(2):175-8
references: 22784121
references: Gene. 2008 Aug 15;420(1):82-9
references: 18565695
references: Science. 2010 Oct 15;330(6002):379-85
references: 20947768
references: Am J Physiol Regul Integr Comp Physiol. 2008 May;294(5):R1675-83
references: 18272659
references: Ann Rheum Dis. 1991 Apr;50(4):243-8
references: 2029206
references: J Cell Physiol. 2013 Feb;228(2):447-56
references: 22740381
references: J Biol Chem. 2003 Jul 4;278(27):24577-85
references: 12730223
references: Osteoarthritis Cartilage. 1997 Jan;5(1):23-37
references: 9010876
references: Science. 1994 Apr 29;264(5159):719-25
references: 8171325
references: Science. 2005 May 13;308(5724):1043-5
references: 15845877
references: Arthritis Res Ther. 2012;14(3):R122
references: 22621205
references: Am J Physiol Regul Integr Comp Physiol. 2008 Dec;295(6):R2059-66
references: 18843095
references: Neuron. 2008 Apr 10;58(1):78-88
references: 18400165
references: J Cell Biochem. 2012 Jul;113(7):2532-42
references: 22415882
references: J Biol Chem. 2007 Apr 13;282(15):11110-21
references: 17311929
references: PLoS One. 2010;5(7):e11527
references: 20634945
references: Science. 2000 Apr 21;288(5465):483-92
references: 10775102
references: Nature. 2012 May 3;485(7396):62-8
references: 22460951
references: Proteomics. 2006 Feb;6(4):1166-74
references: 16421932
references: Obesity (Silver Spring). 2008 Aug;16(8):1887-93
references: 18535539
references: Arthritis Rheum. 2013 Sep;65(9):2334-45
references: 23896777
references: J Biol Chem. 2007 Oct 26;282(43):31409-21
references: 17724016
references: Hum Mol Genet. 2012 Mar 1;21(5):1111-23
references: 22095691
references: Proc Natl Acad Sci U S A. 1993 Apr 1;90(7):2870-4
references: 8464901
references: Annu Rev Physiol. 2010;72:517-49
references: 20148687
references: J Cell Biochem. 2013 Apr;114(4):735-42
references: 23060229
references: Annu Rev Neurosci. 2012;35:445-62
references: 22483041
references: Nat Rev Neurosci. 2003 Aug;4(8):649-61
references: 12894240
references: J Biol Chem. 2003 Jul 11;278(28):25386-94
references: 12734180
references: Hum Mol Genet. 2006 Oct 15;15 Spec No 2:R271-7
references: 16987893
references: J Immunol. 2010 Nov 15;185(10):5796-805
references: 20944004
references: Osteoarthritis Cartilage. 2006 May;14(5):477-85
references: 16431140
references: Am J Physiol Regul Integr Comp Physiol. 2008 Dec;295(6):R2034-40
references: 18843092
references: Arthritis Res. 2001;3(2):107-13
references: 11178118
references: Nat Rev Genet. 2008 Oct;9(10):764-75
references: 18802415
references: Annu Rev Physiol. 2010;72:551-77
references: 20148688
references: Genesis. 2005 Mar;41(3):122-32
references: 15739187
references: Arthritis Rheum. 2012 Jun;64(6):1950-9
references: 22161873
references: Nutr Res Rev. 2010 Jun;23(1):155-68
references: 20122305
references: Proc Natl Acad Sci U S A. 2001 Sep 25;98(20):11114-9
references: 11553773
references: Arthritis Rheum. 2012 Aug;64(8):2611-23
references: 22422036
references: J Pineal Res. 1997 Sep;23(2):72-8
references: 9392445
references: PLoS One. 2013 Jun 18;8(6):e67102
references: 23825629