Melanocortin peptides protect chondrocytes from mechanically induced cartilage injury

作者：Kaneva Magdalena K^*; Kerrigan Mark J P; Grieco Paolo; Curley G Paul; Locke Ian C; Getting Stephen J

来源：Biochemical Pharmacology, 2014, 92(2): 336-347.

DOI：10.1016/j.bcp.2014.08.019

• Cartilage injury
• Mechanical trauma
• Chondrocyte death
• Melanocortin peptides
• Osteoarthritis

Introduction: 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 alpha-MSH and [DTRP8]-gamma-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. %26lt;br%26gt;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 (1.14 N, 6.47 kPa) delivered by a drop tower. Chondroprotective effects of a-MSH, [DTRP8]-gamma-MSH and dexamethasone on cytokine release by TNF-alpha-activated freshly isolated articular chondrocytes/ mechanically injured cartilage explants were investigated by ELISA. %26lt;br%26gt;Results: A single impact to cartilage caused discreet areas of chondrocyte death, accompanied by pro-inflammatory cytokine release; both parameters were modulated by alpha-MSH, [DTRP8]-gamma-MSH and dexamethasone. Melanocortin pre-treatment of TNF-alpha-stimulated freshly isolated ehondrocytes resulted in a bell-shaped inhibition in IL-1 beta, IL-6 and IL-8, and elevation of IL-10 production. The MC314 antagonist, SHU9119, abrogated the effect of [DTRP8]-gamma-MSH but not alpha-MSH on cytokine release. %26lt;br%26gt;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.

• 出版日期2014-11-15