Delayed development of ossification centers in the tibia of prenatal and early postnatal MPS VII mice

Abstract

Short stature is a characteristic feature of most of the mucopolysaccharidoses, a group of inherited lysosomal storage disorders caused by a single enzyme deficiency. MPS patients present with progressive skeletal defects from an early age, including short stature due to impaired cartilage-to-bone conversion (endochondral ossification). The aim of this study was to determine which murine MPS model best reproduces the bone length reduction phenotype of human MPS and use this model to determine the earliest developmental stage when disrupted endochondral ossification first appears. Gus mice representing severe MPS VII displayed the greatest reduction in bone elongation and were chosen for histopathological analysis. Tibial development was assessed from E12.5 to 6 months of age. Chondrocytes in the region of the future primary ossification center became hypertrophic at a similar age to normal in the MPS VII mouse fetus, but a delay in bone deposition was observed with an approximate 1 day delay in the formation of the primary ossification centre. Likewise, chondrocytes in the region of the future secondary ossification center also became hypertrophic at the same age as normal in the MPS VII early postnatal mouse. Bone deposition in the secondary ossification centre was delayed by two days in the MPS VII proximal tibia (observed at postnatal day 14 (P14) compared to P12 in normal). The thickness of the tibial growth plate was larger in MPS VII mice from P9 onwards. Abnormal endochondral ossification starts in utero in MPS VII and worsens with age. It is characterized by a normal timeframe for chondrocyte hypertrophy but a delay in the subsequent deposition of bone in both the primary and secondary ossification centres, accompanied by an increase in growth plate thickness. This suggests that the signals for vascular invasion and bone deposition, some of which are derived from hypertrophic chondrocytes, are altered in MPS VII.

Growth Plate Pathology in the Mucopolysaccharidosis Type VI Rat Model—An Experimental and Computational Approach

“…A similar proliferative zone involvement has been observed in the MPS VII mouse model, which shares dermatan and chondroitin-4-sulphate accumulation with MPS VI. Furthermore, in this model, loss of proliferative chondrocytes was associated with a decrease in cell proliferation, which may be an additional mechanism involved in the alterations observed in MPS VI rats that was not addressed in this study [11,33]. In the MPS VII dog and mouse model, retardation in the development of secondary ossification centers was observed for vertebral bodies and long bones.…”

Mucopolysaccharidosis Type I: A Review of the Natural History and Molecular Pathology

“…To our knowledge, no prenatal studies have been conducted in animal models for MPS I. However, prenatal MPS VII mice show delayed development of ossification centers in the tibia, suggesting an early onset of dysostosis multiplex in this form of MPS [8].…”

Spatially resolved transcriptomic profiling of degraded and challenging fresh frozen samples

“…One of the later developmental stages in this process is the formation of a bony structure called the secondary ossification center (SOC) within the epiphyseal cartilage 28 . In the proximal tibia of humans, this event occurs around birth 29 , whereas in mice it is precisely determined to occur between postnatal day 7 and 11 30 . Within these few days, the SOC contains many different cell-types, including osteoblasts, hematopoietic cells, mesenchymal stromal cells and endothelial cells, which are suddenly located within a few cell-diameters of the resting-zone chondrocytes, potentially influencing these cells 31 .…”