title: Involvement of the Toll-like receptor 4 pathway and use of TNF-alpha antagonists for treatment of the mucopolysaccharidoses.
abstract: Enzyme replacement therapy is currently available for three of the mucopolysaccharidoses (MPSs) but has limited effects on the skeletal lesions. We investigated the involvement of the Toll-like receptor 4 (TLR4) signaling pathway in the pathogenesis of MPS bone and joint disease, and the use of the anti-TNF-alpha drug, Remicade (Centocor, Inc.), for treatment. TLR4 KO (TLR4(lps-/-)) mice were interbred with MPS VII mice to produce double-KO (DKO) animals. The DKO mice had longer and thinner faces and longer femora as revealed by micro-computed tomography analysis compared with MPS VII mice. Histological analyses also revealed more organized and thinner growth plates. The serum levels of TNF-alpha were normalized in the DKO animals, and the levels of phosphorylated STAT1 and STAT3 in articular chondrocytes were corrected. These findings led us to evaluate the effects of Remicade in MPS VI rats. When initiated at 1 month of age, i.v. treatment prevented the elevation of TNF-alpha, receptor activator of NF-kappaB, and other inflammatory molecules not only in the blood but in articular chondrocytes and fibroblast-like synoviocytes (FLSs). Treatment of 6-month-old animals also reduced the levels of these molecules to normal. The number of apoptotic articular chondrocytes in MPS VI rats was similarly reduced, with less infiltration of synovial tissue into the underlying bone. These studies revealed the important role of TLR4 signaling in MPS bone and joint disease and suggest that targeting TNF-alpha may have positive therapeutic effects.
authors.affiliation: Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY 10029, USA. calogera.simonaro@mssm.edu
authors.forename: Calogera M
authors.initials: CM
authors.lastname: Simonaro
authors.forename: Yi
authors.initials: Y
authors.lastname: Ge
authors.forename: Efrat
authors.initials: E
authors.lastname: Eliyahu
authors.forename: Xingxuan
authors.initials: X
authors.lastname: He
authors.forename: Karl J
authors.initials: KJ
authors.lastname: Jepsen
authors.forename: Edward H
authors.initials: EH
authors.lastname: Schuchman
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use; D018501:Antirheumatic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001842:Bone and Bones / Q000033:anatomy & histology / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D006801:Humans; D000069285:Infliximab; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009083:Mucopolysaccharidoses / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000276:immunology; D055114:X-Ray Microtomography
chemical_list: D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab