Melanocortin peptide therapy for the treatment of arthritic pathologies.

Arthritic pathologies are a major cause of morbidity within the western world, with rheumatoid arthritis affecting approximately 1% of adults. This review highlights the therapeutic potential of naturally occurring hormones and their peptides, in both arthritic models of disease and patients. The arthritides represent a group of closely related pathologies in which cytokines, joint destruction, and leukocytes play a causal role. Here we discuss the role of naturally occurring pro-opiomelanocortin (POMC)-derived melanocortin peptides (e.g., alpha melanocyte stimulating hormone [alpha-MSH]) and synthetic derivatives in these diseases. Melanocortins exhibit their biological efficacy by modulating proinflammatory cytokines and subsequent leukocyte extravasation. Their biological effects are mediated via seven transmembrane G-protein-coupled receptors, of which five have been cloned, identified, and termed MC1 to MC5. Adrenocorticotrophic hormone represents the parent molecule of the melanocortins; the first 13 amino acids of which (termed alpha-MSH) have been shown to be the most pharmacologically active region of the parent hormone. The melanocortin peptides have been shown to display potent anti-inflammatory effects in both animal models of disease and patients. The potential anti-inflammatory role for endogenous peptides in arthritic pathologies is in its infancy. The ability to inhibit leukocyte migration, release of cytokines, and induction of anti-inflammatory proteins appears to play an important role in affording protection in arthritic injury, and thus may lead to potential therapeutic targets.

Control of chondrocyte regulatory volume decrease (RVD) by [Ca2+]i and cell shape.

OBJECTIVES: Optimal matrix metabolism by articular chondrocytes is controlled by the 'set-point' volume which is determined mainly by membrane transporters. The signal transduction pathway(s) for the key membrane transporter which responds to cell swelling ('osmolyte channel') and mediates regulatory volume decrease (RVD) is poorly understood, so here the role of Ca2+ and the effects of 2D culture have been clarified. METHODS: Changes to the volume and intracellular calcium levels ([Ca2+]i) of freshly isolated and 2D cultured bovine articular chondrocytes subjected to hypotonic challenge using a 43% reduction in medium osmolarity were studied by single-cell fluorescence microscopy. The effects of ethylene glycol tetraacetic acid (EGTA), REV5901 and Gd(3+) were studied and the role of Ca2+ influx determined by Mn2+ quench. RESULTS: In freshly isolated cells, approximately 50% of chondrocytes exhibited 'robust RVD' (6[120]). RVD was inhibited by REV 5901 (4+/-2% responding) (3[23]) and 2 mM EGTA (18+/-5% responding) (4[166]) whereas Gd3+ had no effect (3[89]). The hypotonic challenge resulted in a Gd3+-insensitive rise in [Ca2+]i that did not correlate with RVD in all cells. Following 2D culture, chondrocytes also demonstrated Gd3+-insensitive RVD, but in contrast, the [Ca2+]i rise was blocked by this agent. CONCLUSIONS: The data suggested that in freshly isolated and 2D cultured chondrocytes, the rise in [Ca2+]i occurring during hypotonic challenge could be related to RVD, but only in some cells. However, with 2D culture, the Ca2+ response switched to being Gd3+-sensitive, suggesting that as a result of changes to chondrocyte shape, stretch-activated cation channels although present, do not appear to play a role in volume regulation.