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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...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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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. |
format | Online Article Text |
id | pubmed-9105101 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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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