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J Cell Physiol. 2015 Sep;230(9):2174-2183. doi: 10.1002/jcp.24946.

Environmental disruption of circadian rhythm predisposes mice to osteoarthritis-like changes in knee joint.

Author information

1
Department of Biochemistry, Rush University Medical Center, Chicago, IL, 60612.
2
Section of Division of Digestive Diseases and Nutrition, Rush University Medical Center, Chicago, IL, 60612.
3
Department of Orthopaedic Surgery, Internal Medicine, Rush University Medical Center, Chicago, IL, 60612.
4
Center for Sleep and Circadian Biology, Department of Neurobiology, Northwestern University, Evanston, IL, 60208.
5
Section of Pharmacology, Rush University Medical Center, Chicago, IL, 60612.
6
Section of Molecular Biophysics and Physiology, Rush University Medical Center, Chicago, IL, 60612.
7
Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Netherlands.
8
Qing-Jun Meng, Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom, M13 9PT.
9
Department of Biochemistry, Vermont Cancer Center for Basic and Translational Research, University of Vermont Medical School, Burlington, VT, USA.
10
Departments of Orthopedic Surgery & Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA.
11
Section of Rheumatology, Rush University Medical Center, Chicago, IL, 60612.
12
Department of Bioengineering, University of Illinois at Chicago, Chicago, IL, 60612.
#
Contributed equally

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.

PMID:
25655021
PMCID:
PMC4447623
DOI:
10.1002/jcp.24946
[Indexed for MEDLINE]
Free PMC Article

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