Chondroprotection by urocortin involves blockade of the mechanosensitive ion channel Piezo1

Lawrence, K.M., Jones, R.C., Jackson, T.R., Baylie, R.L., Abbott, B., Bruhn-Olszewska, B., Board, T.N., Locke, I.C., Richardson, S.M. and Townsend, P.A. 2017. Chondroprotection by urocortin involves blockade of the mechanosensitive ion channel Piezo1. Scientific Reports. 7 (1), p. 5147 5147. https://doi.org/10.1038/s41598-017-04367-4

TitleChondroprotection by urocortin involves blockade of the mechanosensitive ion channel Piezo1
TypeJournal article
AuthorsLawrence, K.M., Jones, R.C., Jackson, T.R., Baylie, R.L., Abbott, B., Bruhn-Olszewska, B., Board, T.N., Locke, I.C., Richardson, S.M. and Townsend, P.A.
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.

Article number5147
JournalScientific Reports
Journal citation7 (1), p. 5147
ISSN2045-2322
Year2017
PublisherNature Publishing Group
Publisher's version
License
CC BY 4.0
File Access Level
Open (open metadata and files)
Digital Object Identifier (DOI)https://doi.org/10.1038/s41598-017-04367-4
Publication dates
Published11 Jul 2017
LicenseCC BY 4.0

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Purification of a streptococcal deoxyribonuclease by affinity chromatography based on a DNA-cellulose matrix
Locke, I.C., Cox, S.F. and Carpenter, B.G. 1997. Purification of a streptococcal deoxyribonuclease by affinity chromatography based on a DNA-cellulose matrix. Journal of Chromatography A. 788 (1-2), pp. 75-80. https://doi.org/10.1016/S0021-9673(97)00695-X

Autoantibodies to myeloperoxidase in systemic sclerosis
Locke, I.C., Worral, J.G., Leaker, B., Black, C.M. and Cambridge, G. 1997. Autoantibodies to myeloperoxidase in systemic sclerosis. Journal of Rheumatology. 24 (1), pp. 86-89.

Characteristics of antibodies to myeloperoxidase in vasculitic and non-vasculitic conditions
Locke, I.C., Leaker, B. and Cambridge, G. 1996. Characteristics of antibodies to myeloperoxidase in vasculitic and non-vasculitic conditions. American College of Rheumatology 60th National Scientific Meeting. Orlando, USA 10/1996

Characteristics of anti-myeloperoxidase autoantibodies in vasculitis and other conditions
Locke, I.C., Leaker, B. and Cambridge, G. 1996. Characteristics of anti-myeloperoxidase autoantibodies in vasculitis and other conditions. American Society of Nephrology 29th Annual Meeting. New Orleans, USA 11/1996

Autoantibodies to neutrophil granule proteins: pathogenic potential in vasculitis?
Locke, I.C. and Cambridge, G. 1996. Autoantibodies to neutrophil granule proteins: pathogenic potential in vasculitis? British Journal of Biomedical Science. 53 (4), pp. 302-316.

A human monoclonal anti-myeloperoxidase antibody can prime human neutrophils in vitro
Cambridge, G., Leaker, B., Locke, I.C., Noronha-Dutra, A. and Epperlein, M. 1996. A human monoclonal anti-myeloperoxidase antibody can prime human neutrophils in vitro. American Society of Nephrology 29th Annual Meeting. New Orleans, USA 11/1996

Autoantibodies to myeloperoxidase in systemic sclerosis
Worral, J.G., Locke, I.C., Leaker, B., Black, C.M. and Cambridge, G. 1995. Autoantibodies to myeloperoxidase in systemic sclerosis. British Society for Rheumatology Heberden Round 1995. Keele University, UK 9/1995

An automated method for the determination of deoxyribonuclease activity as exemplified by fractionation of the components of the medicament Varidase®
Locke, I.C., Ramsay, M.P., Hill, S.S. and Carpenter, B.G. 1993. An automated method for the determination of deoxyribonuclease activity as exemplified by fractionation of the components of the medicament Varidase®. The Journal of Automatic Chemistry. 15 242749.

Automated analysis of the deoxyribonuclease active constituents of the medicament Varidase ®
Locke, I.C., Ramsey, M.P., Hill, S.S. and Carpenter, B.G. 1992. Automated analysis of the deoxyribonuclease active constituents of the medicament Varidase ®. IMLS XX Triennial Conference. Liverpool, UK 9/1992

Purification of the seed lectin from Dolichos biflorus by chromatofocusing
Rogers, D.J., Locke, I.C., Gibbs, R. and Carpenter, B.G. 1990. Purification of the seed lectin from Dolichos biflorus by chromatofocusing. 12th International Lectin Conference. University of Davis, USA 9/1990

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