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    Urocortin-1 is chondroprotective in response to acute cartilage injury via modulation of Piezo1

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    Authors
    Jones, Rebecca C
    Lawrence, Kevin M
    Higgins, Scott M
    Richardson, S M
    Townsend, Paul A
    Affiliation
    Manchester Cancer Research Centre, Division of Cancer Sciences, Faculty of Biology, School of Medical Sciences, Medicine and Health, University of Manchester, Wilmslow Road, Manchester M20 4GJ, UK
    Issue Date
    2022
    
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    Abstract
    Post-traumatic OA (PTOA) is often triggered by injurious, high-impact loading events which result in rapid, excessive chondrocyte cell death and a phenotypic shift in residual cells toward a more catabolic state. As such, the identification of a disease-modifying OA drug (DMOAD) that can protect chondrocytes from death following impact injury, and thereby prevent cartilage degradation and progression to PTOA, would offer a novel intervention. We have previously shown that urocortin-1 (Ucn) is an essential endogenous pro-survival factor that protects chondrocytes from OA-associated pro-apoptotic stimuli. Here, using a drop tower PTOA-induction model, we demonstrate the extent of Ucn's chondroprotective role in cartilage explants exposed to excessive impact load. Using pathway-specific agonists and antagonists, we show that Ucn acts to block load-induced intracellular calcium accumulation through blockade of the non-selective cation channel Piezo1 rather than TRPV4. This protective effect is mediated primarily through the Ucn receptor CRF-R1 rather than CRF-R2. Crucially, we demonstrate that the chondroprotective effect of Ucn is maintained whether it is applied pre-impact or post-impact, highlighting the potential of Ucn as a novel DMOAD for the prevention of injurious impact overload-induced PTOA.
    Citation
    Jones RC, Lawrence KM, Higgins SM, Richardson SM, Townsend PA. Urocortin-1 Is Chondroprotective in Response to Acute Cartilage Injury via Modulation of Piezo1. Vol. 23, International Journal of Molecular Sciences. MDPI AG; 2022. p. 5119.
    Journal
    International Journal of Molecular Sciences
    URI
    http://hdl.handle.net/10541/625306
    DOI
    10.3390/ijms23095119
    PubMed ID
    35563508
    Additional Links
    https://dx.doi.org/10.3390/ijms23095119
    Type
    Article
    Language
    en
    ae974a485f413a2113503eed53cd6c53
    10.3390/ijms23095119
    Scopus Count
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