The circadian clock in murine chondrocytes regulates genes controlling key aspects of cartilage homeostasis

Gossan, Nicole and Zeef, Leo and Hensman, James and Hughes, Alun and Bateman, John F. and Rowley, Lynn and Little, Christopher B. and Piggins, Hugh D. and Rattray, Magnus and Boot-Handford, Raymond P. and Meng, Qing Jun (2013) The circadian clock in murine chondrocytes regulates genes controlling key aspects of cartilage homeostasis. Arthritis and Rheumatism, 65 (9). pp. 2334-2345. ISSN 0004-3591

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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. Conclusion 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.

Item Type:
Journal Article
Journal or Publication Title:
Arthritis and Rheumatism
Uncontrolled Keywords:
?? immunologyimmunology and allergyrheumatologypharmacology (medical) ??
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Deposited On:
25 Jan 2017 11:40
Last Modified:
15 Jul 2024 16:02