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. 2021 Aug;133(4):378-385.
doi: 10.1016/j.ymgme.2021.06.005. Epub 2021 Jun 15.

Progression of vertebral bone disease in mucopolysaccharidosis VII dogs from birth to skeletal maturity

Sun H Peck  1 , Yian Khai Lau  1 , Jennifer L Kang  1 , Megan Lin  1 , Toren Arginteanu  1 , Dena R Matalon  2 , Justin R Bendigo  1 , Patricia O'Donnell  3 , Mark E Haskins  3 , Margret L Casal  3 , Lachlan J Smith  4
Affiliations

Progression of vertebral bone disease in mucopolysaccharidosis VII dogs from birth to skeletal maturity

Sun H Peck et al. Mol Genet Metab. 2021 Aug.

Abstract

Mucopolysaccharidosis (MPS) VII is a lysosomal storage disorder characterized by deficient β-glucuronidase activity, leading to accumulation of incompletely degraded heparan, dermatan and chondroitin sulfate glycosaminoglycans. Patients with MPS VII exhibit progressive spinal deformity, which decreases quality of life. Previously, we demonstrated that MPS VII dogs exhibit impaired initiation of secondary ossification in the vertebrae and long bones. The objective of this study was to build on these findings and comprehensively characterize how vertebral bone disease manifests progressively in MPS VII dogs throughout postnatal growth. Vertebrae were collected postmortem from MPS VII and healthy control dogs at seven ages ranging from 9 to 365 days. Microcomputed tomography and histology were used to characterize bone properties in primary and secondary ossification centers. Serum was analyzed for bone turnover biomarkers. Results demonstrated that not only was secondary ossification delayed in MPS VII vertebrae, but that it progressed aberrantly and was markedly diminished even at 365 days-of-age. Within primary ossification centers, bone volume fraction and bone mineral density were significantly lower in MPS VII at 180 and 365 days-of-age. MPS VII growth plates exhibited significantly lower proliferative and hypertrophic zone cellularity at 90 days-of-age, while serum bone-specific alkaline phosphatase (BAP) was significantly lower in MPS VII dogs at 180 days-of-age. Overall, these findings establish that vertebral bone formation is significantly diminished in MPS VII dogs in both primary and secondary ossification centers during postnatal growth.

Keywords: Biomarker; Canine; Growth plate; Lysosomal storage disease; Mucopolysaccharidosis; Spine.

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Conflict of interest statement

Authors Disclosures

The authors have no relevant conflicts of interest to disclose.

Figures

Figure 1.
Figure 1.
Representative microcomputed tomography reconstructions of T13 vertebrae from control and MPS VII dogs at 9, 14, 30, 42, 90, 180 and 365 days-of-age, illustrating delayed, aberrant and incomplete secondary ossification (purple), reduced bone content in primary ossification centers (gray), and diminished longitudinal growth in MPS VII vertebrae compared to controls. A. Axial (end) view. Scale = 5 mm B. Mid-sagittal view. Scale = 5 mm. Orientation: d = dorsal and v = ventral.
Figure 2.
Figure 2.
Microcomputed tomography analysis of trabecular bone content and architecture in the primary ossification centers of control and MPS VII T13 vertebrae at 90, 180 and 365 days-of-age. A. Bone volume fraction (BV/TV). B. Bone mineral density (BMD). C. Trabecular thickness (Tb.Th). D. Trabecular spacing (Tb.Sp). E. Connectivity density (Conn.Dens). F. Trabecular number (Tb.N). *p≤0.05 vs control; n = 3-5.
Figure 3.
Figure 3.
A. Representative histology of T13 vertebrae control and MPS VII dogs at 90, 180 and 365 days-of-age. Scale = 5 mm; mid-sagittal sections; poc = primary ossification center; soc = secondary ossification center; Alcian blue and picrosirius red staining. B. Higher magnification view of secondary ossification centers (corresponding to region depicted by upper right inset in panel A) showing abnormal persistence of cartilage in MPS VII vertebrae. Scale = 1 mm. C. Higher magnification view of primary ossification centers (corresponding to region depicted by central inset in panel A) showing reduced trabecular bone content in MPS VII vertebrae. Scale = 1 mm.
Figure 4.
Figure 4.
A. Representative histology of growth plates from T13 vertebrae control and MPS VII dogs at 90 and 180 days-of-age. Scale =100 μm; mid-sagittal sections; hematoxylin and eosin staining. Inset shows abnormal growth plate morphology in 6-month-old MPS VII vertebrae. Quantification of B. Proliferative zone (pz) cellularity; C. Hypertrophic zone (hz) cellularity; D. Proliferative zone thickness; and E. Hypertrophic zone thickness. *p≤0.05 vs control; n = 3-5.
Figure 5.
Figure 5.
Serum biomarkers of bone turnover. A. Bone-specific alkaline phosphatase (BAP). B. Pyridinoline/deoxypyridinoline (PYD). C. Glycosaminoglycan (GAG) content. *p≤0.05 vs control; n = 3-5.
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