Chondroprotection by urocortin involves blockade of the mechanosensitive ion channel Piezo1

Abstract Osteoarthritis (OA) is characterised by progressive destruction of articular cartilage and chondrocyte cell death. Here, we show the expression of the endogenous peptide urocortin1 (Ucn1) and two receptor subtypes, CRF-R1 and CRF-R2, in primary human articular chondrocytes (AC) and demonstr...

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Autores principales:	K. M. Lawrence, R. C. Jones, T. R. Jackson, R. L. Baylie, B. Abbott, B. Bruhn-Olszewska, T. N. Board, I. C. Locke, S. M. Richardson, P. A. Townsend
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/57888e6763164f2e881cc57bb81d7732
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spelling	oai:doaj.org-article:57888e6763164f2e881cc57bb81d77322021-12-02T12:32:17ZChondroprotection by urocortin involves blockade of the mechanosensitive ion channel Piezo110.1038/s41598-017-04367-42045-2322https://doaj.org/article/57888e6763164f2e881cc57bb81d77322017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-04367-4https://doaj.org/toc/2045-2322Abstract Osteoarthritis (OA) is characterised by progressive destruction of articular cartilage and chondrocyte cell death. Here, we show the expression of the endogenous peptide urocortin1 (Ucn1) and two receptor subtypes, CRF-R1 and CRF-R2, in primary human articular chondrocytes (AC) and demonstrate its role as an autocrine/paracrine pro-survival factor. This effect could only be removed using the CRF-R1 selective antagonist CP-154526, suggesting Ucn1 acts through CRF-R1 when promoting chondrocyte survival. This cell death was characterised by an increase in p53 expression, and cleavage of caspase 9 and 3. Antagonism of CRF-R1 with CP-154526 caused an accumulation of intracellular calcium (Ca2+) over time and cell death. These effects could be prevented with the non-selective cation channel blocker Gadolinium (Gd3+). Therefore, opening of a non-selective cation channel causes cell death and Ucn1 maintains this channel in a closed conformation. This channel was identified to be the mechanosensitive channel Piezo1. We go on to determine that this channel inhibition by Ucn1 is mediated initially by an increase in cyclic adenosine monophosphate (cAMP) and a subsequent inactivation of phospholipase A2 (PLA2), whose metabolites are known to modulate ion channels. Knowledge of these novel pathways may present opportunities for interventions that could abrogate the progression of OA.K. M. LawrenceR. C. JonesT. R. JacksonR. L. BaylieB. AbbottB. Bruhn-OlszewskaT. N. BoardI. C. LockeS. M. RichardsonP. A. TownsendNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-12 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q K. M. Lawrence R. C. Jones T. R. Jackson R. L. Baylie B. Abbott B. Bruhn-Olszewska T. N. Board I. C. Locke S. M. Richardson P. A. Townsend Chondroprotection by urocortin involves blockade of the mechanosensitive ion channel Piezo1
description	Abstract Osteoarthritis (OA) is characterised by progressive destruction of articular cartilage and chondrocyte cell death. Here, we show the expression of the endogenous peptide urocortin1 (Ucn1) and two receptor subtypes, CRF-R1 and CRF-R2, in primary human articular chondrocytes (AC) and demonstrate its role as an autocrine/paracrine pro-survival factor. This effect could only be removed using the CRF-R1 selective antagonist CP-154526, suggesting Ucn1 acts through CRF-R1 when promoting chondrocyte survival. This cell death was characterised by an increase in p53 expression, and cleavage of caspase 9 and 3. Antagonism of CRF-R1 with CP-154526 caused an accumulation of intracellular calcium (Ca2+) over time and cell death. These effects could be prevented with the non-selective cation channel blocker Gadolinium (Gd3+). Therefore, opening of a non-selective cation channel causes cell death and Ucn1 maintains this channel in a closed conformation. This channel was identified to be the mechanosensitive channel Piezo1. We go on to determine that this channel inhibition by Ucn1 is mediated initially by an increase in cyclic adenosine monophosphate (cAMP) and a subsequent inactivation of phospholipase A2 (PLA2), whose metabolites are known to modulate ion channels. Knowledge of these novel pathways may present opportunities for interventions that could abrogate the progression of OA.
format	article
author	K. M. Lawrence R. C. Jones T. R. Jackson R. L. Baylie B. Abbott B. Bruhn-Olszewska T. N. Board I. C. Locke S. M. Richardson P. A. Townsend
author_facet	K. M. Lawrence R. C. Jones T. R. Jackson R. L. Baylie B. Abbott B. Bruhn-Olszewska T. N. Board I. C. Locke S. M. Richardson P. A. Townsend
author_sort	K. M. Lawrence
title	Chondroprotection by urocortin involves blockade of the mechanosensitive ion channel Piezo1
title_short	Chondroprotection by urocortin involves blockade of the mechanosensitive ion channel Piezo1
title_full	Chondroprotection by urocortin involves blockade of the mechanosensitive ion channel Piezo1
title_fullStr	Chondroprotection by urocortin involves blockade of the mechanosensitive ion channel Piezo1
title_full_unstemmed	Chondroprotection by urocortin involves blockade of the mechanosensitive ion channel Piezo1
title_sort	chondroprotection by urocortin involves blockade of the mechanosensitive ion channel piezo1
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/57888e6763164f2e881cc57bb81d7732
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Chondroprotection by urocortin involves blockade of the mechanosensitive ion channel Piezo1

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