title: The effect of Tlr4 and/or C3 deficiency and of neonatal gene therapy on skeletal disease in mucopolysaccharidosis VII mice.
abstract: Mucopolysaccharidosis (MPS) VII is a lysosomal storage disorder caused by the deficiency of the enzyme β-glucuronidase (Gusb(-/-)) and results in glycosaminoglycan (GAG) accumulation. Skeletal abnormalities include stunted long bones and bone degeneration. GAGs have been hypothesized to activate toll-like receptor 4 (Tlr4) signaling and the complement pathway, resulting in upregulation of inflammatory cytokines that suppress growth and cause degeneration of the bone. Gusb(-/-) mice were bred with Tlr4- and complement component 3 (C3)-deficient mice, and the skeletal manifestations of the doubly- and triply-deficient mice were compared to those of purebred Gusb(-/-) mice. Radiographs showed that purebred Gusb(-/-) mice had shorter tibias and femurs, and wider femurs, compared to normal mice. No improvement was seen in Tlr4, C3, or Tlr4/C3-deficient Gusb(-/-) mice. The glenoid cavity and humerus were scored on a scale from 0 (normal) to +3 (severely abnormal) for dysplasia and bone irregularities, and the joint space was measured. No improvement was seen in Tlr4, C3, or Tlr4/C3-deficient Gusb(-/-) mice, and their joint space remained abnormally wide. Gusb(-/-) mice treated neonatally with an intravenous retroviral vector (RV) had thinner femurs, longer legs, and a narrowed joint space compared with untreated purebred Gusb(-/-) mice, but no improvement in glenohumeral degeneration. We conclude that Tlr4- and/or C3-deficiency fail to ameliorate skeletal abnormalities, and other pathways may be involved. RV treatment improves some but not all aspects of bone disease. Radiographs may be an efficient method for future evaluation, as they readily show glenohumeral joint abnormalities.
authors.affiliation: Department of Internal Medicine, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Xing
authors.affiliation: Department of Internal Medicine, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Wu
authors.affiliation: Department of Internal Medicine, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA; Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA. Electronic address: kponder@dom.wustl.edu.
authors.forename: Katherine P
authors.initials: KP
authors.lastname: Ponder
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001847:Bone Diseases / Q000000981:diagnostic imaging / Q000628:therapy*; D003176:Complement C3 / Q000172:deficiency* / Q000235:genetics; D004195:Disease Models, Animal; D005269:Femur / Q000000981:diagnostic imaging; D015316:Genetic Therapy; D005822:Genetic Vectors; D061165:Glenoid Cavity / Q000000981:diagnostic imaging; D005966:Glucuronidase / Q000235:genetics*; D006811:Humerus / Q000000981:diagnostic imaging; D051379:Mice; D016538:Mucopolysaccharidosis VII / Q000000981:diagnostic imaging / Q000628:therapy*; D009154:Mutation; D011859:Radiography; D013977:Tibia / Q000000981:diagnostic imaging; D051197:Toll-Like Receptor 4 / Q000172:deficiency* / Q000235:genetics
chemical_list: D003176:Complement C3; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D005966:Glucuronidase
keywords: Complement; Degenerative joint disease; Dysostosis multiplex; Gene therapy; Mucopolysaccharidosis; Toll-like receptor