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

Beta-arrestin-1 (beta-arrestin-1) is an adaptor protein that functions in the termination of G-protein activation and seems to be involved in the mediation of the inflammatory response. Interleukin-1 beta (IL-1 beta) elicits the expression of inflammatory mediators through a mechanism involving hyaluronan (HA) degradation, thereby contributing to toll-like receptor 4 (TLR-4) and CD44 activation. Stimulation of both receptors induces nuclear factor kappaB (NF-kB) activation that, through transforming-growth-factor-activated-kinase-1 (TAK-1), in turn stimulates the inflammatory mediators of transcription. As beta-arrestin-1 seems to play an inflammatory role in arthritis, we have investigated the involvement of beta-arrestin-1 in a model of IL-1 beta-induced inflammatory response in mouse chondrocytes. IL-1 beta treatment significantly increases chondrocytes TLR-4, CD44, beta-arrestin-1, TAK-1, and serine/threonine kinase (AKT) mRNA expression and related protein levels. NF-kB is also markedly activated with consequent tumor-necrosis-factor-alpha, interleukin-6, and inducible-nitric-oxide-synthase up-regulation. Treatment of IL-1 beta-stimulated chondrocytes with beta-arrestin-1 and/or AKT and/or TAK-1-specific inhibitors significantly reduces all parameters, although the inhibitory effect exerted by TAK-1-mediated pathways is more effective than that of beta-arrestin-1. beta-Arrestin-1-induced NF-kB activation is mediated by the AKT pathway as shown by IL-1 beta-stimulated chondrocytes treated with AKT inhibitor. Finally, a specific HA-blocking peptide (Pep-1) has confirmed the inflammatory role of degraded HA as a mediator of the IL-1 beta-induced activation of beta-arrestin-1.