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Chondroprotective and anti‐inflammatory role of melanocortin peptides in TNF‐α activated human C‐20/A4 chondrocytes
Author(s) -
Kaneva Magdalena K,
Kerrigan Mark JP,
Grieco Paolo,
Curley G Paul,
Locke Ian C,
Getting Stephen J
Publication year - 2012
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2012.01968.x
Subject(s) - melanocortin , melanocortin receptor , receptor , melanocortins , cytokine , medicine , endocrinology , proinflammatory cytokine , agonist , receptor antagonist , chemistry , tumor necrosis factor alpha , microbiology and biotechnology , inflammation , biology , antagonist
BACKGROUND AND PURPOSE Melanocortin MC 1 and MC 3 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 MC 1 and MC 3 receptors on chondrocytes and the role of α‐melanocyte‐stimulating hormone (α‐MSH) and the selective MC 3 receptor agonist, [DTRP 8 ]‐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, [DTRP 8 ]‐γ‐MSH alone or in the presence of the MC 3/4 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 MC 1,3 receptors. α‐MSH and [DTRP 8 ]‐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 [DTRP 8 ]‐γ‐MSH treatment also inhibited TNF‐α‐induced caspase‐3/7 activation and chondrocyte death. The effects of [DTRP 8 ]‐γ‐MSH, but not α‐MSH, were abolished by the MC 3/4 receptor antagonist, SHU9119. CONCLUSION AND IMPLICATIONS Activation of MC 1 /MC 3 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 MC 1 /MC 3 receptors could be a viable approach for developing chondroprotective and anti‐inflammatory therapies in rheumatoid and osteoarthritis.