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Urocortin-1 Is Chondroprotective in Response to Acute Cartilage Injury via Modulation of Piezo1

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 cho...

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Autores principales: Jones, Rebecca C., Lawrence, Kevin M., Higgins, Scott M., Richardson, Stephen M., Townsend, Paul A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9105101/
https://www.ncbi.nlm.nih.gov/pubmed/35563508
http://dx.doi.org/10.3390/ijms23095119
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author Jones, Rebecca C.
Lawrence, Kevin M.
Higgins, Scott M.
Richardson, Stephen M.
Townsend, Paul A.
author_facet Jones, Rebecca C.
Lawrence, Kevin M.
Higgins, Scott M.
Richardson, Stephen M.
Townsend, Paul A.
author_sort Jones, Rebecca C.
collection PubMed
description 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.
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spelling pubmed-91051012022-05-14 Urocortin-1 Is Chondroprotective in Response to Acute Cartilage Injury via Modulation of Piezo1 Jones, Rebecca C. Lawrence, Kevin M. Higgins, Scott M. Richardson, Stephen M. Townsend, Paul A. Int J Mol Sci Article 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. MDPI 2022-05-04 /pmc/articles/PMC9105101/ /pubmed/35563508 http://dx.doi.org/10.3390/ijms23095119 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Jones, Rebecca C.
Lawrence, Kevin M.
Higgins, Scott M.
Richardson, Stephen M.
Townsend, Paul A.
Urocortin-1 Is Chondroprotective in Response to Acute Cartilage Injury via Modulation of Piezo1
title Urocortin-1 Is Chondroprotective in Response to Acute Cartilage Injury via Modulation of Piezo1
title_full Urocortin-1 Is Chondroprotective in Response to Acute Cartilage Injury via Modulation of Piezo1
title_fullStr Urocortin-1 Is Chondroprotective in Response to Acute Cartilage Injury via Modulation of Piezo1
title_full_unstemmed Urocortin-1 Is Chondroprotective in Response to Acute Cartilage Injury via Modulation of Piezo1
title_short Urocortin-1 Is Chondroprotective in Response to Acute Cartilage Injury via Modulation of Piezo1
title_sort urocortin-1 is chondroprotective in response to acute cartilage injury via modulation of piezo1
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9105101/
https://www.ncbi.nlm.nih.gov/pubmed/35563508
http://dx.doi.org/10.3390/ijms23095119
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