Chondroprotection by urocortin involves blockade of a mechanosensitive piezo1 ion channel: novel, exploitable pathways for the treatment and prevention of osteoarthritis?

Lawrence, K.M., Jones, R.C., Jackson, T.R., Baylie, R.L., Abbot, B., Bruhn-Olszewska, B, Board, T.N., Locke, I.C., Richardson, S.M and Townsend, P.A. 2017. Chondroprotection by urocortin involves blockade of a mechanosensitive piezo1 ion channel: novel, exploitable pathways for the treatment and prevention of osteoarthritis? OARSI 2017 World Congress on Osteoarthritis. Las Vegas, USA. 17 - 20 Apr 2017 Elsevier. doi:10.1016/j.joca.2017.02.124

TitleChondroprotection by urocortin involves blockade of a mechanosensitive piezo1 ion channel: novel, exploitable pathways for the treatment and prevention of osteoarthritis?
AuthorsLawrence, K.M., Jones, R.C., Jackson, T.R., Baylie, R.L., Abbot, B., Bruhn-Olszewska, B, Board, T.N., Locke, I.C., Richardson, S.M and Townsend, P.A.
TypeConference paper
Abstract

Purpose: Currently, the only treatments for Osteoarthritis (OA) are steroidal and non-steroidal anti-inflammatory drugs, and in severe cases total joint replacement surgery. However, these strategies only ameliorate symptoms but do not address the fundamental cause of the disease. Clearly therefore, there is a need for better therapies which address the underlying cause of OA. Importantly, this includes a reduction in the number of viable chondrocytes in articular cartilage, as the severity of cartilage damage has been shown to correlate negatively with the number of remaining chondrocytes. To develop a treatment strategy at a more fundamental level therefore, it is crucial to understand the nature of this chondrocyte cell death. We have previously found that the small endogenous peptide Urocortin (Ucn) and its two cognate G protein coupled receptors (CRF-R1 and CRF-R2) are expressed by human chondrocytes and crucially, its removal from the surrounding milieu using a Ucn depleting antibody or a pan receptor antagonist (as Ucn can bind to both receptor subtypes) causes profound chondrocyte cell death. Therefore, we believe that Ucn is an essential autocrine/paracrine pro-survival factor for human chondrocytes. Here we examine the pathways involved in this chondroprotective effect of Ucn.

Methods: Selective pharmacological antagonists to CRF-R1 (CP-154526, 1–50μM; Tocris) and CRF-R2 (astressin2B 1–50μM; Tocris) were used to determine the receptor subtype responsible for the pro-survival effect of Ucn in human primary articular chondrocytes. Cell death was detected using the Annexin V-FITC Apoptosis Detection Kit I (BD Bioscience) and Western immunoblotting was used to determine the status of pro-apoptotic markers. Downstream signalling pathways involved in antagonist induced cell death were investigated using the adenylate cyclase activator forskolin (0.1μM; Tocris), the phospholipase C (PLC) activator m3M3FBS (0.1μM; Tocris), and the phospholipase A2 (PLA2) inhibitor OBAA (0.1μM; Tocris). Changes in intracellular Ca2+ were detected using Fluo-4 AM permeant dye (Thermo Fisher Scientific) and this effect was studied using the non-selective cation channel blocker Gadolinium (Gd3+ 100μM; Tocris). Human chondrocytes were transfected with siRNAs derived from a selected panel (Dharmacon), to knock down and identify specific ion channel species involved in chondrocyte survival/death.

Results: We found that only inhibition of CRF-R1 using CP 154526 caused antagonist induced cell death, suggesting that the chondrocyte pro-survival effect is caused by Ucn binding to CRF-R1 alone (p < 0.05). This cell death was associated with an increased expression of p53 and cleavage of both caspases 9 and 3 but not caspase 8, implicating the intrinsic apoptotic pathway in this process. Furthermore, we were able to rescue chondrocyte cell death in the presence of antagonist, with the adenylate cyclase activator forskolin and the phospholipase A2 inhibitor OBAA but not with the phospholipase C activator m3M3FBS, suggesting a role for cAMP and PKA activation and a decrease in PLA2 activity in this process. Antagonist induced cell death initially involved a large inward flux of Ca2+ resulting in Ca2+ overload. This inward movement of Ca2+ and subsequent cell death could be prevented by Gd3+ p < 0.05, implying that this process involves a non-selective cation channel and that when Ucn is present, this channel is in a closed conformation. Using an siRNA array panel, we identified Piezo1 as the target ion channel responsible for chondrocyte cell death in the absence of Ucn.

Conclusions: These findings are of great interest because Piezo1 is a novel type of mechanosensor and has recently been found to be highly expressed in chondrocytes and responsible for chondrocyte cell death in a porcine acute mechanical injury model of OA. This is the first study to bring together all of these critical mediators of chondrocyte survival/death and elucidating fully the relationship between Ucn receptor activation and gating of Piezo1, may highlight novel targets as potential therapy nodes for the treatment/prevention of OA. Additionally, because of the crucial role of Ucn in chondrocyte survival, a study of the molecular status of this peptide and/or its receptor could represent novel biomarkers of OA severity and progression.

Year2017
ConferenceOARSI 2017 World Congress on Osteoarthritis
PublisherElsevier
JournalOsteoarthritis and Cartilage
Journal citation25, pp. 69-70
ISSN1063-4584
Digital Object Identifier (DOI)doi:10.1016/j.joca.2017.02.124

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Shah, C.M., Locke, I.C., Chowdrey, H.S. and Gordge, M.P. 2003. Role of protein disulphide isomerase in NO delivery from S-nitrosothiols into megakaryocytes. 4th UK Nitric Oxide Forum. University of Nottingham, UK December 2003

The behaviour of C-20/A4 chondrocytes in 3-D collagen gel cultures
Petsa, A., Afoke, A., Chowdrey, H.S., Knight, R.A., Harris, A. and Locke, I.C. 2003. The behaviour of C-20/A4 chondrocytes in 3-D collagen gel cultures. OARSI 2003 World Congress on Osteoarthritis. Berlin, Germany October 2003 doi:10.1016/S1063-4584(03)00192-4

Ion-dependency of the streptococcal deoxyribonuclease "streptodornase", an active constituent of the medicament Varidase
Locke, I.C. and Carpenter, B.G. 2002. Ion-dependency of the streptococcal deoxyribonuclease "streptodornase", an active constituent of the medicament Varidase. Enzyme and Microbial Technology. 31 (4), pp. 482-489. doi:10.1016/S0141-0229(02)00125-4

Effect of essential oils and their components on cell
Prashar, A., Veness, R., Locke, I.C. and Evans, C.S. 2002. Effect of essential oils and their components on cell. Future Trends in Phytochemistry. Gargnano, Italy

Varidase: the science behind the medicament
Rutter, P.M., Carpenter, B.G., Hill, S.S. and Locke, I.C. 2000. Varidase: the science behind the medicament. Journal of Wound Care. 9 (5), pp. 223-226.

A comparison of the characteristics of circulating anti-myeloperoxidase antibodies in vasculitis with those in non-vasculitic conditions
Locke, I.C., Leaker, B. and Cambridge, G. 1999. A comparison of the characteristics of circulating anti-myeloperoxidase antibodies in vasculitis with those in non-vasculitic conditions. Clinical and Experimental Immunology. 115 (2), pp. 369-376. doi:10.1046/j.1365-2249.1999.00809.x

A comparison of the variable region genes of two human monoclonal antibodies to myeloperoxidase
Locke, I.C., Rahman, M.A.A. and Cambridge, G. 1998. A comparison of the variable region genes of two human monoclonal antibodies to myeloperoxidase. British Society for Immunology 6th Annual Meeting. Harrogate, UK 12/1998

Adjacent proline residues in the inhibitory domain of the Oct-2 transcription factor play distinct functional roles
Liu, Y.Z., Lee, I.K., Locke, I.C., Dawson, S. and Latchman, D. 1998. Adjacent proline residues in the inhibitory domain of the Oct-2 transcription factor play distinct functional roles. Nucleic Acids Research. 26 (10), pp. 2464-2472. doi:10.1093/nar/26.10.2464

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. doi: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

Automated analysis of the deoxyribonuclease active constituents of the medicament Varidase ®
Locke, I.C., Ramsay, M.P., Hill, S.S. and Carpenter, B.G. 1993. Automated analysis of the deoxyribonuclease active constituents of the medicament Varidase ®. The Journal of Automatic Chemistry. 15, pp. 65-70.

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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