Osteoarthritis: the role and mechanisms of the chondroprotective peptide Urocortin I

White, O.B. 2011. Osteoarthritis: the role and mechanisms of the chondroprotective peptide Urocortin I. PhD thesis University of Westminster School of Life Sciences

TitleOsteoarthritis: the role and mechanisms of the chondroprotective peptide Urocortin I
TypePhD thesis
AuthorsWhite, O.B.
Abstract

Osteoarthritis (OA), a chronic degenerative condition of the diarthrodial joints is most predominant amongst the middle aged and elderly population, where it is

associated with progressive disability and deformity of the joints. Whilst the exact mechanism of OA pathogenesis is currently unknown, chondrocyte death by

apoptosis is seen as one of the main contributors to the disease process. It is

increasingly recognised that the overproduction of mediators such as Nitric Oxide (NO) in Osteoarthritic cartilage contributes to the disease pathology partly by

inducing chondrocyte apoptosis. Therefore, agents, which protect against NOinduced mitochondrial injury, may have therapeutic potential in Osteoarthritis.

The CRF related peptide, Urocortin I (UCNI), has been shown to protect the

human chondrocyte cell line, C-20/A4, from SNAP/NO induced apoptotic death,

but little is yet known about its mechanism of action. Therefore the aim of this project is to investigate the potential mechanism through which UCNI exerts its

observed protective effects. The studies documented here, have demonstrated

the endogenous expression of this cytoprotective peptide, UCNI, by C-20/A4

chondrocytes and have shown that treatment of chondrocytes with SNAP (a NO

donor) resulted in a significant increase in apoptosis which was abrogated by the addition of exogenous UCNI. Therefore, an investigation into the potential

mechanism for UCNI mediated protection against apoptosis in chondrocytes (i.e.

chondroprotection) detected the mRNA expression of both CRFR1 and CRFR2

receptors specifically the CRFR1α and CRFR2β splice variants by the C-20/A4

chondrocytes. However the CRFR antagonist, α−helical CRH failed to induce

apoptosis or abrogate the protective effects of UCNI against SNAP/NO induced

apoptosis. RT-PCR studies have also demonstrated C-20/A4 mRNA expression

of the Kir6.1, Kir6.2, SUR1 and SUR2B subunits of the KATP channels suggesting

that functional KATP channels are also present in these cells, which represent a further putative mechanism of action for UCNI.

Quantitative PCR studies were performed to determine regulation of CRFR and

Kir6.1 expression by UCNI. These studies showed that treatment of chondrocytes

with UCNI and SNAP alone and concurrently resulted in no significant change in

mRNA expression of either CRF receptors or kir6.1 (the pore forming subunit of

the mitochondrial KATP channel). Treatment of chondrocytes with Diazoxide, a

mitochondrial KATP channel opener, resulted in a reduction in SNAP induced

apoptosis, mimicking that seen for UCNI, suggesting a similar protective role for these channels in chondrocytes, to that proposed in other cell types and

supporting these channels as potential targets for UCNI in chondroprotection.

Year2011
FileOmeco_Bianco_WHITE.pdf
Publication dates
Completed2011

Related outputs

Urocortin protects chondrocytes from NO-induced apoptosis: a future therapy for osteoarthritis?
Intekhab Alam, N.Y., White, O.B., Getting, S.J., Petsa, A., Knight, R.A., Townsend, P.A., Lawrence, K.M. and Locke, I.C. 2013. Urocortin protects chondrocytes from NO-induced apoptosis: a future therapy for osteoarthritis? Cell Death and Disease. 4, p. e717.

Chondrocyte CRF receptor expression and Urocortin I mediated chondroprotection
White, O.B., Intekhab-Alam, N.Y., Chowdrey, H.S., Knight, R.A., Locke, I.C. and Intekhab Alam, N.Y. 2011. Chondrocyte CRF receptor expression and Urocortin I mediated chondroprotection. Rheumatology 2011. Brighton, UK 12th-14th April 2011

Mechanisms of Urocortin family peptide mediated chondroprotection
White, O.B., Intekhab Alam, N.Y., Chowdrey, H.S., Knight, R.A. and Locke, I.C. 2010. Mechanisms of Urocortin family peptide mediated chondroprotection. OARSI 2010 World Congress on Osteoarthritis. Brussels, Belgium September 23-26, 2010

The effect of indentor shape on the creep curves of collagen gel
Locke, I.C., White, O.B., Trwoga, P. and Afoke, A. 2010. The effect of indentor shape on the creep curves of collagen gel. OARSI 2010 World Congress on Osteoarthritis. Brussels, Belgium September 23-26, 2010

Permalink - https://westminsterresearch.westminster.ac.uk/item/900z8/osteoarthritis-the-role-and-mechanisms-of-the-chondroprotective-peptide-urocortin-i


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