Inflammatory signaling sensitizes Piezo1 mechanotransduction in articular chondrocytes as a pathogenic feed-forward mechanism in osteoarthritis.
Abstract
Osteoarthritis (OA) is a painful and debilitating condition of synovial joints without
any disease-modifying therapies [A. M. Valdes, T. D. Spector, Nat. Rev. Rheumatol. 7, 23-32 (2011)]. We previously identified mechanosensitive PIEZO channels, PIEZO1
and PIEZO2, both expressed in articular cartilage, to function in chondrocyte mechanotransduction
in response to injury [W. Lee et al., Proc. Natl. Acad. Sci. U.S.A. 111, E5114-E5122 (2014); W. Lee, F. Guilak, W. Liedtke, Curr. Top. Membr. 79, 263-273 (2017)]. We therefore asked whether interleukin-1-mediated inflammatory
signaling, as occurs in OA, influences Piezo gene expression and channel function, thus indicative of maladaptive reprogramming
that can be rationally targeted. Primary porcine chondrocyte culture and human osteoarthritic
cartilage tissue were studied. We found that interleukin-1α (IL-1α) up-regulated Piezo1
in porcine chondrocytes. Piezo1 expression was significantly increased in human osteoarthritic
cartilage. Increased Piezo1 expression in chondrocytes resulted in a feed-forward
pathomechanism whereby increased function of Piezo1 induced excess intracellular Ca2+ at baseline and in response to mechanical deformation. Elevated resting state Ca2+ in turn rarefied the F-actin cytoskeleton and amplified mechanically induced deformation
microtrauma. As intracellular substrates of this OA-related inflammatory pathomechanism,
in porcine articular chondrocytes exposed to IL-1α, we discovered that enhanced Piezo1
expression depended on p38 MAP-kinase and transcription factors HNF4 and ATF2/CREBP1.
CREBP1 directly bound to the proximal PIEZO1 gene promoter. Taken together, these signaling and genetic reprogramming events represent
a detrimental Ca2+-driven feed-forward mechanism that can be rationally targeted to stem the progression
of OA.
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https://hdl.handle.net/10161/22727Published Version (Please cite this version)
10.1073/pnas.2001611118Publication Info
Lee, Whasil; Nims, Robert J; Savadipour, Alireza; Zhang, Qiaojuan; Leddy, Holly A;
Liu, Fang; ... Liedtke, Wolfgang B (2021). Inflammatory signaling sensitizes Piezo1 mechanotransduction in articular chondrocytes
as a pathogenic feed-forward mechanism in osteoarthritis. Proceedings of the National Academy of Sciences of the United States of America, 118(13). pp. e2001611118-e2001611118. 10.1073/pnas.2001611118. Retrieved from https://hdl.handle.net/10161/22727.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.
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Show full item recordScholars@Duke
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 combi
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.
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 mech
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