Beta-arrestin 1 is involved in the catabolic response stimulated by hyaluronan degradation in mouse chondrocytes

Beta-Arrestin-1 is an adaptor protein that leads to termination of G protein activation and seems involved in the mediation of inflammatory response. Interleukin-1beta (IL-1beta) elicits the expression of inflammatory mediators through a mechanism involving Hyaluronan (HA) degradation that contributes to toll-like receptor 4 (TLR-4) and CD44 activation. Stimulation of both receptors induces nuclear factor kappaB (NF-kB) activation that, through the transforming growth-factor-activated-kinase-1, (TAK-1), in turn stimulates the inflammatory mediators transcription. As beta-Arrestin-1 seems to play an inflammatory role in arthritis, we aimed to investigate the involvement of beta-Arrestin-1 in a model of IL-1beta-induced inflammatory response in mouse chondrocytes. IL-1beta treatment significantly increased chondrocytes TLR-4, CD44, beta-Arrestin-1, TAK-1, and serine/threonine kinase (AKT) mRNA expression and related protein levels. NF-kB was also markedly activated with consequent Tumour-Necrosis-Factor-alpha, interleukin-6 and Inducible-Nitric-Oxide-Synthase up-regulation. Treatment of IL-1beta-stimulated chondrocytes with beta-Arrestin-1 or/and AKT or/and TAK-1 specific inhibitors significantly reduced all parameters, although the inhibitory effect exerted by TAK-1 mediated pathways was more effective than that of beta-Arrestin-1. Beta-Arrestin-1 induced NF-kB activation was mediated by AKT pathway as shown by IL-1beta stimulated chondrocytes treated with AKT inhibitor. Finally a specific HA blocking peptide (Pep-1) confirmed the inflammatory role of degraded HA as mediator of IL-1beta-induced activation of beta-Arrestin-1.