title: Chondroprotective and anti-inflammatory role of melanocortin peptides in TNF-α activated human C-20/A4 chondrocytes.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: School of Life Sciences, University of Westminster, London, UK.
authors.forename: Magdalena K
authors.initials: MK
authors.lastname: Kaneva
authors.forename: Mark J P
authors.initials: MJ
authors.lastname: Kerrigan
authors.forename: Paolo
authors.initials: P
authors.lastname: Grieco
authors.forename: G Paul
authors.initials: GP
authors.lastname: Curley
authors.forename: Ian C
authors.initials: IC
authors.lastname: Locke
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Getting
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D019902:Chondrocytes / Q000187:drug effects* / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D006801:Humans; D020782:Matrix Metalloproteinases / Q000378:metabolism; D009074:Melanocyte-Stimulating Hormones / Q000494:pharmacology*; D020011:Protective Agents / Q000494:pharmacology*; D044102:Receptor, Melanocortin, Type 1 / Q000378:metabolism; D044104:Receptor, Melanocortin, Type 3 / Q000378:metabolism; D000521:alpha-MSH / Q000494:pharmacology*; D019825:gamma-MSH / Q000494:pharmacology*
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; C505392:MC3R protein, human; D020011:Protective Agents; D044102:Receptor, Melanocortin, Type 1; D044104:Receptor, Melanocortin, Type 3; D019825:gamma-MSH; C103272:SHU 9119; D000521:alpha-MSH; D009074:Melanocyte-Stimulating Hormones; D000242:Cyclic AMP; D053148:Caspase 3; D053179:Caspase 7; D020782:Matrix Metalloproteinases; D015232:Dinoprostone