Enhanced cartilage regeneration in MIA/CD-RAP deficient mice

Melanoma inhibitory activity/cartilage-derived retinoic acid-sensitive protein (MIA/CD-RAP) is a small soluble protein secreted from chondrocytes. It was identified as the prototype of a family of extracellular proteins adopting an SH3 domain-like fold. In order to study the consequences of MIA/CD-RAP deficiency in detail we used mice with a targeted gene disruption of MIA/CD-RAP (MIA−/−) and analyzed cartilage organisation and differentiation in in vivo and in vitro models. Cartilage formation and regeneration was determined in models for osteoarthritis and fracture healing in vivo, in addition to in vitro studies using mesenchymal stem cells of MIA−/− mice. Interestingly, our data suggest enhanced chondrocytic regeneration in the MIA−/− mice, modulated by enhanced proliferation and delayed differentiation. Expression analysis of cartilage tissue derived from MIA−/− mice revealed strong downregulation of nuclear RNA-binding protein 54-kDa (p54nrb), a recently described modulator of Sox9 activity. In this study, we present p54nrb as a mediator of MIA/CD-RAP to promote chondrogenesis. Taken together, our data indicate that MIA/CD-RAP is required for differentiation in cartilage potentially by regulating signaling processes during differentiation

Comparing the efficacy of a web-assisted calprotectin-based treatment algorithm (IBD-live) with usual practices in teenagers with inflammatory bowel disease:study protocol for a randomized controlled trial

Background: To prevent clinical relapse in teenagers with inflammatory bowel disease (IBD) there is a need to monitor disease activity continuously. Timely optimisation of medical treatment may nip a preclinical relapse in the bud and change the natural course of IBD. Traditionally, disease monitoring is done during scheduled visits, but this is when most teenagers report full control. IBD care could be more efficient if patients were seen at times of clinical need. This study aims to examine the effectiveness of a web-assisted calprotectin-based treatment algorithm (IBD-live) compared with usual practices in teenagers with IBD. Methods/design: A randomized trial of web-based disease monitoring versus usual care is conducted at 10 Dutch IBD care centers. We plan to recruit 180 patients between 10-and 19-years old with quiescent IBD at baseline. Teenagers assigned to IBD-live will use the flarometer -an automatic cumulation of disease activity and fecal calprotectin measurements-to estimate probability of relapse. In case the flarometer indicates high risk the patient requires treatment intensification in accordance with national guidelines; low risk means that maintenance therapy is unchanged; and intermediate risk requires optimisation of drug adherence. Patients assigned to usual practice get the best accepted medical care with regular health checks. Primary outcome is the frequency of relapse at 52 weeks of follow-up. The diagnosis of relapse is based on a clinical activity index score >10 points necessitating remission induction therapy. Secondary outcomes include quality of life and cost-effectiveness. Discussion: Web-assisted monitoring of disease activity with rapid access for those with acute relapse may allow teenagers to develop skills that are required of adult patients (including communication and self-determination). Similar monitoring systems have been introduced for teenagers with asthma and diabetes, with a positive effect on disease control, but the intervention has not been evaluated in teenagers with IBD. A randomized trial in adult patients with ulcerative colitis showed that a web-assisted treatment algorithm is feasible, safe and cost-effective. Results of the current trial are expected to have important implications for teenagers with IBD that incurs substantial health burdens and economic costs

Activated leukocyte cell adhesion molecule (ALCAM/CD166): signaling at the divide of melanoma cell clustering and cell migration?

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Antagonism of p66shc by melanoma inhibitory activity

The p66shc protein governs oxidant stress and mammalian lifespan. Here, we identify melanoma inhibitory activity (MIA), a protein secreted by melanoma cells, as a novel binding partner and antagonist of p66shc. The N-terminal collagen homology-2 (CH2) domain of p66shc binds to the Src Homology-3 (SH3)-like domain of MIA in vitro. In cells, ectopically expressed MIA and p66shc colocalize and co-precipitate. MIA also co-precipitates with the CH2 domain of p66shc in vivo. MIA expression in vivo suppresses p66shc-stimulated increase in endogenous hydrogen peroxide (H2O2), and inhibits basal and H2O2-induced phosphorylation of p66shc on serine 36 and H2O2-induced death. In human melanoma cells expressing MIA, endogenous MIA and p66shc co-precipitate. Downregulation of MIA in melanoma cells increases basal and ultraviolet radiation (UVR)-induced phosphorylation of p66shc on serine 36, augments endogenous H2O2 levels, and increases their susceptibility to UVR-induced death. These findings show that MIA binds to p66shc, and suggest that this interaction antagonizes phosphorylation and function of p66shc