Synergy between Piezo1 and Piezo2 channels confers high-strain mechanosensitivity to articular cartilage.
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.
Departments of Neurology.
Whasil
W
Lee
Orthopaedic Surgery, and.
Holly A
HA
Leddy
Departments of Neurology.
Yong
Y
Chen
Departments of Neurology.
Suk Hee
SH
Lee
Orthopaedic Surgery, and.
Nicole A
NA
Zelenski
Orthopaedic Surgery, and.
Amy L
AL
McNulty
Neurobiology, and.
Jason
J
Wu
Department of Physics and Astronomy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599; and.
Kellie N
KN
Beicker
Department of Mechanical Engineering and Materials Science, Duke University, Durham, NC 27708;
Jeffrey
J
Coles
Department of Mechanical Engineering and Materials Science, Duke University, Durham, NC 27708;
Stefan
S
Zauscher
Neurobiology, and.
Jörg
J
Grandl
Department of Physiology and Biophysics, State University of New York, Buffalo, NY 14214.
Frederick
F
Sachs
Orthopaedic Surgery, and Department of Mechanical Engineering and Materials Science, Duke University, Durham, NC 27708; wolfgang@neuro.duke.edu guilak@duke.edu.
Farshid
http://orcid.org/0000-0001-7380-0330
F
Guilak
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.
Wolfgang B
WB
Liedtke
D000818:Animals; D020013:Calcium Signaling; D002358:Cartilage, Articular / Q000502:physiology*; D019902:Chondrocytes / Q000502:physiology; D007473:Ion Channels / Q000235:genetics / Q000502:physiology*; D051379:Mice; D034741:RNA, Small Interfering; D013314:Stress, Mechanical
D007473:Ion Channels; C552920:Piezo1 protein, mouse; C552921:Piezo2 protein, mouse; D034741:RNA, Small Interfering
Piezo; cartilage; cartilage injury; chondrocyte; mechanotransduction