The chondrocyte clock gene Bmal1 controls cartilage homeostasis and integrity
Michal Dudek, … , Ray P. Boot-Handford, Qing-Jun Meng
Michal Dudek, … , Ray P. Boot-Handford, Qing-Jun Meng
Published December 14, 2015
Citation Information: J Clin Invest. 2016;126(1):365-376. https://doi.org/10.1172/JCI82755.
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Research Article Aging Bone biology

The chondrocyte clock gene Bmal1 controls cartilage homeostasis and integrity

Abstract

Osteoarthritis (OA) is the most prevalent and debilitating joint disease, and there are currently no effective disease-modifying treatments available. Multiple risk factors for OA, such as aging, result in progressive damage and loss of articular cartilage. Autonomous circadian clocks have been identified in mouse cartilage, and environmental disruption of circadian rhythms in mice predisposes animals to OA-like damage. However, the contribution of the cartilage clock mechanisms to the maintenance of tissue homeostasis is still unclear. Here, we have shown that expression of the core clock transcription factor BMAL1 is disrupted in human OA cartilage and in aged mouse cartilage. Furthermore, targeted Bmal1 ablation in mouse chondrocytes abolished their circadian rhythm and caused progressive degeneration of articular cartilage. We determined that BMAL1 directs the circadian expression of many genes implicated in cartilage homeostasis, including those involved in catabolic, anabolic, and apoptotic pathways. Loss of BMAL1 reduced the levels of phosphorylated SMAD2/3 (p-SMAD2/3) and NFATC2 and decreased expression of the major matrix-related genes Sox9, Acan, and Col2a1, but increased p-SMAD1/5 levels. Together, these results define a regulatory mechanism that links chondrocyte BMAL1 to the maintenance and repair of cartilage and suggest that circadian rhythm disruption is a risk factor for joint diseases such as OA.

Authors

Michal Dudek, Nicole Gossan, Nan Yang, Hee-Jeong Im, Jayalath P.D. Ruckshanthi, Hikari Yoshitane, Xin Li, Ding Jin, Ping Wang, Maya Boudiffa, Ilaria Bellantuono, Yoshitaka Fukada, Ray P. Boot-Handford, Qing-Jun Meng

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Figure 4

RNA-seq results from cartilage of 8- to 10-week-old WT and Col2a1 Bmal1–/– littermates.

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RNA-seq results from cartilage of 8- to 10-week-old WT and Col2a1 Bmal1–...
(A) Heatmap depicting expression levels and patterns of the genes identified as significantly different between WT and Col2a1 Bmal1–/– cartilages. In total, 5,506 genes were dysregulated in KO cartilages at 1 or more of the 4 time points studied (log2 fold change >1; adjusted P value < 0.05). White bars represent day; black bars represent night. (B) GO term analysis of the differentially expressed genes. Selective BMAL1-regulated pathways that are potentially relevant to cartilage homeostasis and OA were plotted against their significant levels (–log P value). A positive z-score suggests possible upregulation, while a negative z-score suggests possible downregulation. (C) Several classic BMAL1-regulated clock genes identified in this study were validated by qPCR in mouse cartilage tissue. Data represent the mean ± SEM and were normalized to WT at 5 am and are expressed as relative fold changes (n = 4 animals/time point). All genes tested followed the expression pattern identified by RNA-seq. **P < 0.01 and ***P < 0.001, by 2-tailed Student’s t test.