anti-tnf-alpha therapy enhances the effects of enzyme replacement therapy in rats with mucopolysaccharidosis type vianti-tnf-alpha疗法提高了酶替代疗法的效果与黏多糖病大鼠输入vi.pdf

Anti-TNF-Alpha Therapy Enhances the Effects of Enzyme Replacement Therapy in Rats with Mucopolysaccharidosis Type VI 1 2 1 2 1 Efrat Eliyahu , Theodore Wolfson , Yi Ge , Karl J. Jepsen , Edward H. Schuchman , Calogera M. Simonaro1* 1 Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, New York, United States of America, 2 Department of Orthopaedics, Mount Sinai School of Medicine, New York, New York, United States of America Abstract Background: Although enzyme replacement therapy (ERT) is available for several lysosomal storage disorders, the benefit of this treatment to the skeletal system is very limited. Our previous work has shown the importance of the Toll-like receptor 4/ TNF-alpha inflammatory pathway in the skeletal pathology of the mucopolysaccharidoses (MPS), and we therefore undertook a study to examine the additive benefit of combining anti-TNF-alpha therapy with ERT in a rat model of MPS type VI. Methodology/Principal Findings: MPS VI rats were treated for 8 months with NaglazymeH (recombinant human N-acetyl- galactosamine-4-sulfatase), or by a combined protocol using NaglazymeH and the rat-specific anti-TNF-alpha drug, CNTO1081. Both protocols led to markedly reduced serum levels of TNF-alpha and RANKL, although only the combined treatment reduced TNF-alpha in the articular cartilage. Analysis of cultured articular chondrocytes showed that the combination therapy also restored collagen IIA1 expression, and reduced expression of the apoptotic marker, PARP. Motor activity and mobility were improved by ERT, and these were significantly enhanced by combination treatment. Tracheal deformities