title: Melanocortin peptides protect chondrocytes from mechanically induced cartilage injury.
abstract: BACKGROUND
  Mechanical injury can greatly influence articular cartilage, propagating inflammation, cell injury and death - risk factors for the development of osteoarthritis. Melanocortin peptides and their receptors mediate anti-inflammatory and pro-resolving mechanisms in chondrocytes. This study aimed to investigate the potential chondroprotective properties of α-MSH and [DTRP(8)]-γ-MSH in mechanically injured cartilage explants, their ability to inhibit pro-inflammatory and stimulate anti-inflammatory cytokines in in situ and in freshly isolated articular chondrocytes.
  
  
  METHODS
  The effect of melanocortins on in situ chondrocyte viability was investigated using confocal laser scanning microscopy of bovine articular cartilage explants, subjected to a single blunt impact (1.14N, 6.47 kPa) delivered by a drop tower. Chondroprotective effects of α-MSH, [DTRP(8)]-γ-MSH and dexamethasone on cytokine release by TNF-α-activated freshly isolated articular chondrocytes/mechanically injured cartilage explants were investigated by ELISA.
  
  
  RESULTS
  A single impact to cartilage caused discreet areas of chondrocyte death, accompanied by pro-inflammatory cytokine release; both parameters were modulated by α-MSH, [DTRP(8)]-γ-MSH and dexamethasone. Melanocortin pre-treatment of TNF-α-stimulated freshly isolated chondrocytes resulted in a bell-shaped inhibition in IL-1β, IL-6 and IL-8, and elevation of IL-10 production. The MC3/4 antagonist, SHU9119, abrogated the effect of [DTRP(8)]-γ-MSH but not α-MSH on cytokine release.
  
  
  CONCLUSIONS
  Melanocortin peptide pre-treatment prevented chondrocyte death following mechanical impact to cartilage and led to a marked reduction of pro-inflammatory cytokines, whilst prompting the production of anti-inflammatory/pro-resolving cytokine IL-10. Development of small molecule agonists towards melanocortin receptors could thus be a viable approach for preventing chondrocyte inflammation and death within cartilage and represent an alternative approach for the treatment of osteoarthritis.
authors.affiliation: Faculty of Science and Technology, University of Westminster, 115 New Cavendish Street, London W1W 6UW, United Kingdom. Electronic address: m.kaneva@qmul.ac.uk.
authors.forename: Magdalena K
authors.initials: MK
authors.lastname: Kaneva
authors.affiliation: Faculty of Health, Social Care & Education, Anglia Ruskin University, Cambridge CB1 1PT, United Kingdom.
authors.forename: Mark J P
authors.initials: MJ
authors.lastname: Kerrigan
authors.affiliation: Department of Chemistry, University of Naples, Naples, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Grieco
authors.affiliation: Faculty of Science and Technology, University of Westminster, 115 New Cavendish Street, London W1W 6UW, United Kingdom.
authors.forename: G Paul
authors.initials: GP
authors.lastname: Curley
authors.affiliation: Faculty of Science and Technology, University of Westminster, 115 New Cavendish Street, London W1W 6UW, United Kingdom.
authors.forename: Ian C
authors.initials: IC
authors.lastname: Locke
authors.affiliation: Faculty of Science and Technology, University of Westminster, 115 New Cavendish Street, London W1W 6UW, United Kingdom.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Getting
mesh_terms: D000818:Animals; D002358:Cartilage, Articular / Q000187:drug effects / Q000293:injuries* / Q000378:metabolism*; D002417:Cattle; D002478:Cells, Cultured; D019902:Chondrocytes / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism*; D055595:Mechanical Phenomena / Q000187:drug effects; D053486:Melanocortins / Q000494:pharmacology*; D009924:Organ Culture Techniques; D000521:alpha-MSH / Q000494:pharmacology
chemical_list: D018836:Inflammation Mediators; D053486:Melanocortins; D000521:alpha-MSH
keywords: Cartilage injury; Chondrocyte death; Mechanical trauma; Melanocortin peptides; Osteoarthritis