Kaneva, Magdalena K., Kerrigan, Mark J.P., Grieco, Paolo, Curley, G. Paul, Locke, Ian C. and Getting, Stephen J. (2012) Chondroprotective and anti-inflammatory role of melanocortin peptides in TNF-α activated human C-20/A4 chondrocytes. British Journal of Pharmacology, 167 (1). pp. 67-79. ISSN 0007-1188 (doi:10.1111/j.1476-5381.2012.01968.x)

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Abstract

BACKGROUND AND PURPOSE: Melanocortin MC1 and MC3 receptors, mediate the anti-inflammatory effects of melanocortin peptides. Targeting these receptors could therefore lead to development of novel anti-inflammatory therapeutic agents. We investigated the expression of MC1 and MC3 receptors on chondrocytes and the role of α-melanocyte-stimulating hormone (α-MSH) and the selective MC3 receptor agonist, [DTRP8]-γ-MSH, in modulating production of inflammatory cytokines, tissue-destructive proteins and induction of apoptotic pathway(s) in the human chondrocytic C-20/A4 cells.
EXPERIMENTAL APPROACH: Effects of α-MSH, [DTRP8]-γ-MSH alone or in the presence of the MC3/4 receptor antagonist, SHU9119, on TNF-α induced release of pro-inflammatory cytokines, MMPs, apoptotic pathway(s) and cell death in C-20/A4 chondrocytes were investigated, along with their effect on the release of the anti-inflammatory cytokine IL-10.
KEY RESULTS: C-20/A4 chondrocytes expressed functionally active MC1,3 receptors. α-MSH and [DTRP8]-γ-MSH treatment, for 30 min before TNF-α stimulation, provided a time-and-bell-shaped concentration-dependent decrease in pro-inflammatory cytokines (IL-1β, IL-6 and IL-8) release and increased release of the chondroprotective and anti-inflammatory cytokine, IL-10, whilst decreasing expression of MMP1, MMP3, MMP13 genes.α-MSH and [DTRP8]-γ-MSH treatment also inhibited TNF-α-induced caspase-3/7 activation and chondrocyte death. The effects of [DTRP8]-γ-MSH, but not α-MSH, were abolished by the MC3/4 receptor antagonist, SHU9119.
CONCLUSION AND IMPLICATIONS: Activation of MC1/MC3 receptors in C-20/A4 chondrocytes down-regulated production of pro-inflammatory cytokines and cartilage-destroying proteinases, inhibited initiation of apoptotic pathways and promoted release of chondroprotective and anti-inflammatory cytokines. Developing small molecule agonists to MC1/MC3 receptors could be a viable approach for developing chondroprotective and anti-inflammatory therapies in rheumatoid and osteoarthritis.

Item Type:	Article
Additional Information:	[1] Article first published online: 3 AUG 2012, Accepted manuscript online: 3 APR 2012. [2] ISSN 0007-1188 (Print), 1476-5381 (Online). [3] British Journal of Pharmacology is a journal of The British Pharmacological Society.
Uncontrolled Keywords:	anti-inflammatory, apoptosis, caspases, chemokines, chondrocyte, chondroprotective, cytokines, GPCR, melanocortins, MMPs
Subjects:	R Medicine > RM Therapeutics. Pharmacology
Pre-2014 Departments:	School of Science
Related URLs:	Publisher
Last Modified:	26 Oct 2016 10:38
URI:	http://gala.gre.ac.uk/id/eprint/9299

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