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

TitleSynergy between Piezo1 and Piezo2 channels confers high-strain mechanosensitivity to articular cartilage.
Publication TypeJournal Article
Year of Publication2014
AuthorsW Lee, HA Leddy, Y Chen, SH Lee, NA Zelenski, AL McNulty, J Wu, KN Beicker, J Coles, S Zauscher, J Grandl, F Sachs, F Guilak, and WB Liedtke
JournalProc Natl Acad Sci U S A
Volume111
Issue47
Start PageE5114
PaginationE5114 - E5122
Date Published11/2014
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 Ca(2+) signals and electrical currents compared with single-Piezo expression. In primary articular chondrocytes, mechanically evoked Ca(2+) 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.

DOI10.1073/pnas.1414298111
Short TitleProc Natl Acad Sci U S A