Osteoarthritis (OA) is characterized by a slow and progressive deterioration of articular cartilage, likely arises from a combination of systemic and environmental factors. Growing evidence show that environmental factors that chronically upset circadian rhythms, can cause myriad of metabolic disorders, including the metabolic syndrome, diabetes and cancer. However, the pathophysiological role of circadian disruption in articular cartilage homeostasis and degenerative joint disease remains to be established. The novelty of our study is to identify chronic circadian disruption as a risk factor for the development of OA. Our study, for the first time, show that disruption of the circadian clock system in mice predisposes to pathological changes in the knee joint as reflected by proteoglycan (PG) loss, fibrillation, upregulation of matrix-degrading enzyme production and concomitant downregulation of chondrogenic factors. We also show that key catabolic signaling pathways, which are known to be involved in human knee OA, are responsible for developing OA-like pathological features in knee joints of circadian-disrupted mice. In particular, articular chondrocytes of circadian-disrupted mice exhibit significant 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. Our findings suggest a possible link between environmental chronic circadian dysfunction, such as that experienced by night shift workers and people who regularly cross multiple time zones, and the development of OA over time. As chronic circadian rhythm disruption is a common feature in modern day society, our findings open new perspectives on the role of chronic circadian rhythm disruption in the development OA and may have potential implications on translational and cost-effective approaches for musculoskeletal treatment strategies in the future.
Kc R1, Li X1, Voigt RM2, Ellman MB1,3, Summa KC4, Vitaterna MH4, Keshavarizian A2,5,6,7, Turek FW4, Meng QJ8,Stein GS9, van Wijnen AJ10, Chen D1, Forsyth CB2, Im HJ1,3,11,12,13.
J Cell Physiol. 2015 Sep;230(9):2174-83.[expand title=”Show Affiliations”]
1Department of Biochemistry, Rush University Medical Center, Chicago, Illinois.
2Division of Digestive Diseases and Nutrition, Rush University Medical Center, Chicago, Illinois.
3Department of Orthopaedic Surgery, Internal Medicine, Rush University Medical Center, Chicago, Illinois.
4Center for Sleep and Circadian Biology, Department of Neurobiology, Northwestern University, Evanston, Illinois.
5Department of Pharmacology, Rush University Medical Center, Chicago, Illinois.
6Department of Molecular Biophysics and Physiology, Rush University Medical Center, Chicago, Illinois.
7Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Netherlands.
8Qing-Jun Meng, Faculty of Life Sciences, University of Manchester, Manchester, M13 9PT, United Kingdom.
9Department of Biochemistry, Vermont Cancer Center for Basic and Translational Research, University of Vermont Medical School, Burlington, Vermont.
10Department of Orthopedic Surgery & Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota.
11Section of Rheumatology, Rush University Medical Center, Chicago, Illinois.
12Department of Bioengineering, University of Illinois at Chicago, Chicago, Illinois.
13Jesse Brown Veterans Affair, Chicago, Illinois.[/expand]
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 pathologicalchanges 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.
© 2015 Wiley Periodicals, Inc.