TY - JOUR
T1 - Postnatal progression of bone disease in the cervical spines of mucopolysaccharidosis I dogs
AU - Chiaro, Joseph A.
AU - Baron, Matthew D.
AU - del Alcazar, Chelsea M.
AU - O'Donnell, Patricia
AU - Shore, Eileen M.
AU - Elliott, Dawn M.
AU - Ponder, Katherine P.
AU - Haskins, Mark E.
AU - Smith, Lachlan J.
N1 - Funding Information:
This work was funded by a grant from the University of Pennsylvania Center for Orphan Diseases Research and Therapy , and grants from the NIH ( P40 OD010939 , P30 AR050950 and R01 DK066448 ). The authors thank Dr Sherry Liu for technical advice on microCT analyses. Author contributions to this study were as follows: LJS and JAC contributed to conceptual design, performed experiments and drafted the manuscript; MDB, CDA and PO performed experiments and critically revised the manuscript for important intellectual content; MEH contributed to conceptual design, supervised raising of the animals, performed post-mortems and critically revised the manuscript for important intellectual content; EMS, KPP and DME contributed to conceptual design and critically revised the manuscript for important intellectual content. All authors approved the final version of the manuscript prior to submission. MEH owns stock in BioMarin Pharmaceuticals, Inc.
PY - 2013/7
Y1 - 2013/7
N2 - Introduction: Mucopolysaccharidosis I (MPS I) is a lysosomal storage disorder characterized by deficient α- l-iduronidase activity leading to accumulation of poorly degraded dermatan and heparan sulfate glycosaminoglycans (GAGs). MPS I is associated with significant cervical spine disease, including vertebral dysplasia, odontoid hypoplasia, and accelerated disk degeneration, leading to spinal cord compression and kypho-scoliosis. The objective of this study was to establish the nature and rate of progression of cervical vertebral bone disease in MPS I using a canine model. Methods: C2 vertebrae were obtained post-mortem from normal and MPS I dogs at 3, 6 and 12. months-of-age. Morphometric parameters and mineral density for the vertebral trabecular bone and odontoid process were determined using micro-computed tomography. Vertebrae were then processed for paraffin histology, and cartilage area in both the vertebral epiphyses and odontoid process were quantified. Results: Vertebral bodies of MPS I dogs had lower trabecular bone volume/total volume (BV/TV), trabecular thickness (Tb.Th), trabecular number (Tb.N) and bone mineral density (BMD) than normals at all ages. For MPS I dogs, BV/TV, Tb.Th and BMD plateaued after 6. months-of-age. The odontoid process appeared morphologically abnormal for MPS I dogs at 6 and 12. months-of-age, although BV/TV and BMD were not significantly different from normals. MPS I dogs had significantly more cartilage in the vertebral epiphyses at both 3 and 6. months-of-age. At 12. months-of-age, epiphyseal growth plates in normal dogs were absent, but in MPS I dogs they persisted. Conclusions: In this study we report reduced trabecular bone content and mineralization, and delayed cartilage to bone conversion in MPS I dogs from 3. months-of-age, which may increase vertebral fracture risk and contribute to progressive deformity. The abnormalities of the odontoid process we describe likely contribute to increased incidence of atlanto-axial subluxation observed clinically. Therapeutic strategies that enhance bone formation may decrease incidence of spine disease in MPS I patients.
AB - Introduction: Mucopolysaccharidosis I (MPS I) is a lysosomal storage disorder characterized by deficient α- l-iduronidase activity leading to accumulation of poorly degraded dermatan and heparan sulfate glycosaminoglycans (GAGs). MPS I is associated with significant cervical spine disease, including vertebral dysplasia, odontoid hypoplasia, and accelerated disk degeneration, leading to spinal cord compression and kypho-scoliosis. The objective of this study was to establish the nature and rate of progression of cervical vertebral bone disease in MPS I using a canine model. Methods: C2 vertebrae were obtained post-mortem from normal and MPS I dogs at 3, 6 and 12. months-of-age. Morphometric parameters and mineral density for the vertebral trabecular bone and odontoid process were determined using micro-computed tomography. Vertebrae were then processed for paraffin histology, and cartilage area in both the vertebral epiphyses and odontoid process were quantified. Results: Vertebral bodies of MPS I dogs had lower trabecular bone volume/total volume (BV/TV), trabecular thickness (Tb.Th), trabecular number (Tb.N) and bone mineral density (BMD) than normals at all ages. For MPS I dogs, BV/TV, Tb.Th and BMD plateaued after 6. months-of-age. The odontoid process appeared morphologically abnormal for MPS I dogs at 6 and 12. months-of-age, although BV/TV and BMD were not significantly different from normals. MPS I dogs had significantly more cartilage in the vertebral epiphyses at both 3 and 6. months-of-age. At 12. months-of-age, epiphyseal growth plates in normal dogs were absent, but in MPS I dogs they persisted. Conclusions: In this study we report reduced trabecular bone content and mineralization, and delayed cartilage to bone conversion in MPS I dogs from 3. months-of-age, which may increase vertebral fracture risk and contribute to progressive deformity. The abnormalities of the odontoid process we describe likely contribute to increased incidence of atlanto-axial subluxation observed clinically. Therapeutic strategies that enhance bone formation may decrease incidence of spine disease in MPS I patients.
KW - Development
KW - Glycosaminoglycans
KW - Mucopolysaccharidosis
KW - Odontoid process
KW - Spine
KW - Trabecular bone
UR - http://www.scopus.com/inward/record.url?scp=84877026416&partnerID=8YFLogxK
U2 - 10.1016/j.bone.2013.03.014
DO - 10.1016/j.bone.2013.03.014
M3 - Article
C2 - 23563357
AN - SCOPUS:84877026416
SN - 8756-3282
VL - 55
SP - 78
EP - 83
JO - Bone
JF - Bone
IS - 1
ER -