The chondrocyte clock gene Bmal1 controls cartilage homeostasis and integrity.

Research output: Contribution to journalArticle

  • External authors:
  • Nicole Gossan
  • Nan Yang
  • Hee-Jeong Im
  • Jayalath P D Ruckshanthi
  • Hikari Yoshitane
  • Xin Li
  • Ding Jin
  • Maya Boudiffa
  • Ilaria Bellantuono
  • Yoshitaka Fukada

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.

Bibliographical metadata

Original languageEnglish
Pages (from-to)365-376
Number of pages12
JournalJournal of Clinical Investigation
Volume126
Issue number1
Early online date14 Dec 2015
DOIs
Publication statusPublished - 4 Jan 2016

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