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

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.

Department

Description

Provenance

Citation

Published Version (Please cite this version)

10.1073/pnas.1414298111

Publication Info

Lee, Whasil, Holly A Leddy, Yong Chen, Suk Hee Lee, Nicole A Zelenski, Amy L McNulty, Jason Wu, Kellie N Beicker, et al. (2014). Synergy between Piezo1 and Piezo2 channels confers high-strain mechanosensitivity to articular cartilage. Proc Natl Acad Sci U S A, 111(47). pp. E5114–E5122. 10.1073/pnas.1414298111 Retrieved from https://hdl.handle.net/10161/12971.

This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.

Scholars@Duke

Leddy

Holly Leddy

Research & Dev Engineer III
Chen

Yong Chen

Associate Professor in Neurology

Dr. Yong Chen is an Associate Professor of Neurology at the Duke University School of Medicine.  He is also affiliated with Duke Anesthesiology-Center for Translational Pain Medicine (CTPM) and Duke-Pathology.

The Chen lab mainly studies sensory neurobiology of pain and itch, with a focus on TRP ion channels and neural circuits. The main objective of our lab is to identify molecular and cellular mechanisms underlying chronic pain and chronic-disease associated itch, using a combination of animal behavioral, genetic, molecular and cellular, advanced imaging, viral, and optogenetic approaches.  There are three major research areas in the lab: craniofacial pain, arthritis pain and joint function, and systemic-disease associated itch.

McNulty

Amy Lynn McNulty

Associate Professor in Orthopaedic Surgery

The McNulty Lab is working to develop strategies to prevent osteoarthritis and to promote tissue repair and regeneration following joint injury. In order to accomplish this, we are working in three main areas.  1) We are working to understand the pathways that are activated by normal and injurious mechanical loading of cartilage and meniscus and how these mechanotransduction pathways are altered during aging, injury, and tissue degeneration. A greater understanding of alterations in mechanosensitive signaling mechanisms with aging and injury will likely reveal potential targets to promote tissue repair and prevent tissue degeneration and osteoarthritis development. 2) We are developing meniscus tissue engineered constructs that will be utilized to repair and replace meniscus tissue lost due to injury and surgical resection.  3)  We are focusing on the biological and biomechanical changes that occur in the joint following meniscus injury and how these may contribute to osteoarthritis development.   

Zauscher

Stefan Zauscher

Professor in the Thomas Lord Department of Mechanical Engineering and Materials Science

My research lies at the intersection of surface and colloid science, polymer materials engineering, and biointerface science, with four central areas of focus:

  1. Fabrication, manipulation and characterization of stimulus-responsive biomolecular and bio-inspired polymeric nanostructures on surfaces;
  2. Nanotechnology of soft-wet materials and hybrid biological/non-biological microdevices;
  3. Receptor-ligand interactions relevant to the diagnostics of infectious diseases;
  4. Friction of soft-wet materials, specifically the role of glycoproteins on friction in diarthroidal joints.

These four broad lines of inquiry deal with fundamental behaviors of soft-wet materials on surfaces and interfaces. The design and fabrication of these interfaces using "smart" polymeric and biomolecular nanostructures, and the characterization of the resulting structures, are critically important for the development of biomolecular sensors and devices and for bioinspired materials. Key approaches and tools I use in my research are: bottom-up organization on the molecular scale, through self-assembly, in-situ polymerization, and manipulation of intermolecular interactions; topdown fabrication, through scanning probe nanolithography; stimulus-responsive polymers; molecular recognition; and new approaches to sensing and manipulation. This research supports Duke's Pratt School of Engineering strategic initiative to expand research in soft-wet Materials Science.

Grandl

Jorg Grandl

Associate Professor of Neurobiology

I am a biophysicist, Associate Professor of Neurobiology, and Director of Neurobiology Graduate Studies at Duke University. I received my PhD from the Ecole Polytéchnique Fédérale de Lausanne (EPFL), Switzerland and completed an NIH Ruth L. Kirschstein Postdoctoral Fellowship with Nobel Laureate Ardem Patapoutian at Scripps, La Jolla.

My research investigates the biophysics of force-gated ion channels and cellular mechanotransduction. This work produced over 30 publications, including in Nature, Nature Neuroscience, Neuron, and eLife. My past trainees have continued scientific training at academic institutions such as Harvard, The Broad Institute, MD Anderson, and Yale, or in the private biomedical sector. Further, I served on study sections for NIH R01, R03, R35, R00/K99, F32 and P20 awards, and for the German Research Foundation (DFG) Emmy Noether Award, and I regularly peer-review manuscripts for Nature, Science, Neuron, eLife, PNAS, and others.

As the Director of Duke Neurobiology Graduate Studies, I currently serve 47 intellectually diverse faculty from 15 Departments, who hold over $42M (or $900K per investigator) in research support, and 67 graduate trainees, who over the past 5 years have published 130 research articles and won 31 individual fellowships. In this capacity I oversee, coordinate, and direct all daily aspects of the Duke Neurobiology Graduate Training Program.

Liedtke

Wolfgang Bernhard Liedtke

Adjunct Professor in the Department of Neurology

Research Interests in the Liedtke-Lab:

  • Pain/ nociception
  • Sensory transduction and -transmission
  • TRP ion channels
  • Water and salt equilibrium regulated by the central nervous system



Visit the lab's website, download papers and read Dr. Liedtke's CV here.

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