TY - JOUR
T1 - The effect of Tlr4 and/or C3 deficiency and of neonatal gene therapy on skeletal disease in mucopolysaccharidosis VII mice
AU - Xing, Elizabeth M.
AU - Wu, Susan
AU - Ponder, Katherine P.
N1 - Publisher Copyright:
© 2014 Elsevier Inc.
PY - 2015/2/1
Y1 - 2015/2/1
N2 - 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.
AB - 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.
KW - Complement
KW - Degenerative joint disease
KW - Dysostosis multiplex
KW - Gene therapy
KW - Mucopolysaccharidosis
KW - Toll-like receptor
UR - http://www.scopus.com/inward/record.url?scp=84921662593&partnerID=8YFLogxK
U2 - 10.1016/j.ymgme.2014.12.305
DO - 10.1016/j.ymgme.2014.12.305
M3 - Article
C2 - 25559179
AN - SCOPUS:84921662593
SN - 1096-7192
VL - 114
SP - 209
EP - 216
JO - Molecular genetics and metabolism
JF - Molecular genetics and metabolism
IS - 2
ER -