Postnatal progression of bone disease in the cervical spines of mucopolysaccharidosis I dogs

Abstract

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 disc 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 TMD 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.

Pathogenesis and treatment of spine disease in the mucopolysaccharidoses

“…Studies using the naturally-occurring canine models of MPS I and MPS VII have described similar failures of ossification in the peripheral regions the vertebral bodies [8, 106]. At 6 weeks-of-age, there is clear evidence of delayed and dysregulated bone formation in the secondary ossification centers of the vertebrae, as well as elevated GAG content within the annulus fibrosus that persist into older ages in MPS VII dogs (Figure 2).…”

“…At 6 weeks-of-age, there is clear evidence of delayed and dysregulated bone formation in the secondary ossification centers of the vertebrae, as well as elevated GAG content within the annulus fibrosus that persist into older ages in MPS VII dogs (Figure 2). In the vertebral secondary ossification centers of 6 month-old MPS VII dogs, elevated levels of GAGs and reduced calcium indicated the presence of cartilage rather than bone [106]. Biomechanical evaluations showed that vertebral endplates adjacent to these cartilaginous lesions are mechanically extremely weak, leading to reduced stiffness and hypermobility of the intervertebral joints, implicating these lesions in the progression of deformity [105].…”

“…These lesions persist for the lifetime of the animals (up to 11 years) [116]. MPS I dogs also exhibit uncalcified lesions in the vertebrae during growth, and while peripheral zones eventually fully calcify, aberrant regions of cartilage of varying magnitude in the vicinity of the growth plate persist into skeletal maturity [106]. MPS I and VII dogs display additional vertebral abnormalities, including widening, and beaking at the vertebral rims [128].…”

“…For example, MPS I dogs exhibit significantly lower vertebral trabecular BMD and bone volume fraction from as early as 3 months of age [106], a trend that is also seen in MPS VI cats [108]. In contrast to humans and large animal models, rodent models of MPS have been reported to exhibit increased trabecular bone mass with increasing age and disease progression [69, 144].…”

Generalised vertebral abnormalities in a Rhodesian ridgeback with a lysosomal storage disease

“…MPS I is associated with vertebral abnormalities, similar to those observed in the dog of this report. These include generalised abnormalities most prominent in the cervical region and are characterised by trabecular bone loss, delayed cartilage to bone conversion, vertebral dysplasia, collapsed intervertebral disc spaces, intervertebral disc herniation and increased fracture risk (Chiaro and others 2013). The dog presented in this report also suffered from long-standing elbow disease.…”