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 2

Deletion of chondrocyte Bmal1 leads to cartilage-specific loss of circadian rhythm.

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Deletion of chondrocyte Bmal1 leads to cartilage-specific loss of circad...
(A) Representative BMAL1 IHC (brown) in WT (n = 3 animals/group) and Col2a1 Bmal1–/– (n = 4) mouse knee joints. Graph shows quantification of BMAL1-positive cells. Data represent the mean ± SEM. Cells were counted across the entire tibial plateau of anatomically equivalent sections and are expressed as a percentage of WT littermates. ***P < 0.001, by 2-tailed Student’s t test. Scale bars: 100 μm. (B) PER2::luc bioluminescence recordings from SCN and peripheral tissues of WT and Col2a1 Bmal1–/– littermates. n = 4 representative traces. cps, counts per second. (C) Wheel-running activity records of WT and Col2a1 Bmal1–/– littermates under LD or DD conditions. Actograms were double plotted. Upper bar denotes a 12-hour light (gray)/12-hour dark (black) (LD) schedule. Shaded area denotes constant darkness (DD). Black vertical lines denote significant activity in 10-minute bins. Figure shows a representative sample from 1 littermate pair. The experiment was conducted with 6 pairs.