The chondrocyte clock gene Bmal1 controls cartilage homeostasis and integrity

J Clin Invest. 2016 Jan;126(1):365-76. doi: 10.1172/JCI82755. Epub 2015 Dec 14.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • ARNTL Transcription Factors / analysis
  • ARNTL Transcription Factors / physiology*
  • Animals
  • Cartilage, Articular / metabolism*
  • Chondrocytes / physiology*
  • Circadian Rhythm / physiology*
  • Homeostasis / physiology*
  • Humans
  • Male
  • Mice
  • Mice, Knockout
  • NFATC Transcription Factors / physiology
  • Osteoarthritis / etiology*
  • Sequence Analysis, RNA
  • Transforming Growth Factor beta / physiology


  • ARNTL Transcription Factors
  • BMAL1 protein, human
  • NFATC Transcription Factors
  • Transforming Growth Factor beta