Melanocortin peptides are endogenously produced peptides originating from the posttranslational processing of the pro-opiomelanocortin hormone (POMC), exerting their effect by binding to class A G-protein-coupled 7 transmembrane domain receptors, positively coupled to adenylate cyclase. To date five melanocortin receptors have been identified and termed MC1 to MC5. MC1 and MC3 have previously been proposed to exert anti-inflammatory effects by modulating the host inflammatory response. The expression and the functional activity of both receptors was identified and confirmed in the C-20/A4 chondrocyte cell-line, isolated primary bovine and in situ bovine articular chondrocytes. Pro-inflammatory cytokines including IL-1β, IL-6, IL-8, TNF-α, produced by activated articular chondrocytes significantly up-regulate matrix metalloproteinases (MMPs) gene expression, and inhibit the chondrocyte’s compensatory synthesis pathways required to restore the integrity of the degraded extracellular matrix (ECM). Human C-20/A4 and primary bovine articular chondrocytes were found to produce CC and CXC chemokines, which induced the release of matrix degrading enzymes and activated cell apoptotic pathways. TNF-α significantly up-regulated the expression of pro-inflammatory cytokines and chemokines IL-1β, IL-6, IL-8, MCP-1 and MMP1 and 13 from C-20/A4 cell line and freshly isolated primary bovine articular chondrocytes. An effect attenuated in the presence of α-MSH and D[TRP]8-γ-MSH. The MC3/4 antagonist SHU9119 blocked the effects of D[TRP]8-γ-MSH but not α-MSH. TNF-α (60.0 pg/ml) stimulation caused ~30% cell death and was partially, but significantly inhibited by treatment of the cells with the melanocortin peptides. The antiinflammatory and chondroprotective effect of melanocortin peptides were then tested on in situ bovine articular chondrocytes, injured by a single blunt impact delivered by a drop tower. The mechanical injury caused significant cell death and up-regulation of the proinflammatory cytokines IL-6 and IL-8, which were significantly reduced on pre-treatment of cartilage explants with melanocortin peptides. Modulation of pro-inflammatory pathways and inflammation-modulated cartilage destruction with subsequent chondrocyte apoptosis appears to be logical development in the potential medical therapy of OA. The small molecular weight of melanocortin peptides should facilitate the absorption from the GI tract and the movement to the cartilage matrix, which together with creative drug delivery methods might potentially prove to be potent therapeutic agents in the future.