Melanocortin peptides protect chondrocytes from mechanically induced cartilage injury

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 [DTRP8]-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, 6.47kPa) delivered by a drop tower. Chondroprotective effects of α-MSH, [DTRP8]-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, [DTRP8]-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 [DTRP8]-γ-MSH but not α-MSH on cytokine release. CONCLUSION: 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