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Proc Natl Acad Sci U S A. 2014 Nov 25;111(47):E5114-22. doi: 10.1073/pnas.1414298111. Epub 2014 Nov 10.

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

Author information

1
Departments of Neurology.
2
Orthopaedic Surgery, and.
3
Neurobiology, and.
4
Department of Physics and Astronomy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599; and.
5
Department of Mechanical Engineering and Materials Science, Duke University, Durham, NC 27708;
6
Department of Physiology and Biophysics, State University of New York, Buffalo, NY 14214.
7
Orthopaedic Surgery, and Department of Mechanical Engineering and Materials Science, Duke University, Durham, NC 27708; wolfgang@neuro.duke.edu guilak@duke.edu.
8
Departments of Neurology, Neurobiology, and Clinics for Pain and Palliative Care, Duke University Medical Center, Durham, NC 27710; wolfgang@neuro.duke.edu guilak@duke.edu.

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.

KEYWORDS:

Piezo; cartilage; cartilage injury; chondrocyte; mechanotransduction

PMID:
25385580
PMCID:
PMC4250098
DOI:
10.1073/pnas.1414298111
[Indexed for MEDLINE]
Free PMC Article

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