Synergy between Piezo1 and Piezo2 channels confers high-strain mechanosensitivity to articular cartilage

Whasil Lee, Holly A. Leddy, Yong Chen, Suk Hee Lee, Nicole A. Zelenski, Amy L. McNulty, Jason Wu, Kellie N. Beicker, Jeffrey Coles, Stefan Zauscher, Jörg Grandl, Frederick Sachs, Farshid Guilak, Wolfgang B. Liedtke

Research output: Contribution to journalArticle

106 Scopus citations

Abstract

Diarthrodial joints are essential for load bearing and locomotion. Physiologically, articular cartilage sustains millions of cycles of mechanical loading. Chondrocytes, the cells in cartilage, regulate their metabolic activities in response to mechanical loading. Pathological mechanical stress can lead to maladaptive cellular responses and subsequent cartilage degeneration. We sought to deconstruct chondrocyte mechanotransduction by identifying mechanosensitive ion channels functioning at injurious levels of strain. We detected robust expression of the recently identified mechanosensitive channels, PIEZO1 and PIEZO2. Combined directed expression of Piezo1 and -2 sustained potentiated mechanically induced Ca2+ signals and electrical currents compared with single-Piezo expression. In primary articular chondrocytes, mechanically evoked Ca2+ transients produced by atomic force microscopy were inhibited by GsMTx4, a PIEZO-blocking peptide, and by Piezo1- or Piezo2-specific siRNA. We complemented the cellular approach with an explant-cartilage injury model. GsMTx4 reduced chondrocyte death after mechanical injury, suggesting a possible therapy for reducing cartilage injury and posttraumatic osteoarthritis by attenuating Piezo-mediated cartilage mechanotransduction of injurious strains.

Original languageEnglish
Pages (from-to)E5114-E5122
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number47
DOIs
StatePublished - Nov 25 2014

Keywords

  • Cartilage
  • Cartilage injury
  • Chondrocyte
  • Mechanotransduction
  • Piezo

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    Lee, W., Leddy, H. A., Chen, Y., Lee, S. H., Zelenski, N. A., McNulty, A. L., Wu, J., Beicker, K. N., Coles, J., Zauscher, S., Grandl, J., Sachs, F., Guilak, F., & Liedtke, W. B. (2014). Synergy between Piezo1 and Piezo2 channels confers high-strain mechanosensitivity to articular cartilage. Proceedings of the National Academy of Sciences of the United States of America, 111(47), E5114-E5122. https://doi.org/10.1073/pnas.1414298111