Reduced SIRT1 activity and levels during osteoarthritis (OA), promotes gradual loss of cartilage. Loss of cartilage matrix is accompanied by an increase of matrix metalloproteinase 13 (MMP13), partially due to enhanced LEF1 transcriptional activity. Here we assess the role of SIRT1 in LEF1-mediated MMP13 gene expression in human osteoarthritic chondrocytes. Results show that MMP13 protein levels and enzymatic activity decreased significantly during SIRT1 overexpression or activation by resveratrol. Conversely, MMP13 gene expression was reduced in chondrocytes transfected with SIRT1 siRNA or treated with nicotinamide (NAM), a sirtuin inhibitor. Chondrocytes challenged with IL-1β, a cytokine involved in OA pathogenesis, enhanced LEF1 protein levels and gene expression, resulting in increased MMP13 gene expression, however, overexpression of SIRT1 during IL-1β challenge impeded LEF1 levels and MMP13 gene expression. While previous reports showed that LEF1 binds to the MMP13 promoter and transactivates its expression, we observed that SIRT1 repressed LEF1 protein and mRNA expression, ultimately reducing LEF1 transcriptional activity, as judged by luciferase assay. Finally, mice articular cartilage from Sirt1 nulls presented increased LEF1 and MMP13 protein levels, similar to human OA cartilage. Thus, demonstrating for the first time that SIRT1 represses MMP13 in human OA chondrocytes, which appears to be mediated, at least in part, through repression of the transcription factor LEF1, a known modulator of MMP13 gene expression.
New Lower Strength of Auvi-Q Approved for Use in Young Children
Auvi-Q® (epinephrine injection) received FDA approval on November 20, 2017, to treat pediatric patients who weigh between ( pounds) and 25Kg (33 pounds). It is an auto-injector that delivers a smaller dose of epinephrine to block allergic reactions. Because it is designed for use in small children, the injector needle is shorter and the dose is smaller than in other Auvi-Q devices. The new injector has a voice feature that announces each step in the directions for use. Like Auvi-Q and 3mg auto-injectors, the lower dose will be dispensed in cartons containing two devices pre-filled with active drug and one inactive practice device. Detailed instructions are included with each prescription as well. Kaléo, Auvi-Q’s manufacturer, has not released its launch or pricing plans. Prescribing information can be found here .