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Enhanced osteoblastic differentiation of parietal bone in a novel murine model of mucopolysaccharidosis type II
Narutoshi Yamazaki1,2, Mari Ohira1, Shuji Takada3
1Department of Clinical Laboratory Medicine, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535, Japan.
Abstract:
Mucopolysaccharidosis type II (MPS II, OMIM 309900) is an X-linked disorder caused by a deficiency of lysosomal enzyme iduronate-2-sulfatase (IDS). The clinical manifestations of MPS II involve cognitive decline, bone deformity, and visceral disorders. These manifestations are closely associated with IDS enzyme activity, which catalyzes the stepwise degradation of heparan sulfate and dermatan sulfate. In this study, we established a novel Ids-deficient mice and further assessed the enzyme's physiological role. Using DNA sequencing, we found a genomic modification of the Ids genome, which involved the deletion of a 138-bp fragment spanning from intron 2 to exon 3, along with the insertion of an adenine at the 5' end of exon 3 in the mutated allele. Consistent with previous data, our Ids-deficient mice showed an attenuated enzyme activity and an enhanced accumulation of glycosaminoglycans. Interestingly, we noticed a distinct enlargement of the calvarial bone in both neonatal and young adult mice. Our examination revealed that Ids deficiency led to an enhanced osteoblastogenesis in the parietal bone, a posterior part of the calvarial bone originating from the paraxial mesoderm and associated with an enhanced expression of osteoblastic makers, such as Col1a and Runx2. In sharp contrast, cell proliferation of the parietal bone in these mice appeared similar to that of wild-type controls. These results suggest that the deficiency of Ids could be involved in an augmented differentiation of calvarial bone, which is often noticed as an enlarged head circumference in MPS II-affected individuals.
Insights
Mucopolysaccharidosis type II (MPS II) is an X-linked disorder caused by a deficiency in the enzyme iduronate-2-sulfatase (IDS). This study reveals that IDS deficiency in mice leads to enhanced calvarial bone development, contributing to enlarged head circumference in MPS II patients.
Area of Science:
- Genetics and Molecular Biology
- Developmental Biology
- Biochemistry
Background:
- Mucopolysaccharidosis type II (MPS II) is an X-linked genetic disorder resulting from deficient iduronate-2-sulfatase (IDS) enzyme activity.
- This deficiency leads to the accumulation of glycosaminoglycans (GAGs), causing progressive multi-systemic manifestations including skeletal deformities and cognitive decline.
- The precise mechanisms linking IDS deficiency to specific skeletal abnormalities, such as calvarial bone changes, require further elucidation.
Purpose of the Study:
- To establish and characterize a novel mouse model of Ids deficiency.
- To investigate the physiological role of the IDS enzyme in skeletal development, specifically focusing on calvarial bone.
- To explore the molecular mechanisms underlying bone abnormalities observed in MPS II.
Main Methods:
- Generation of Ids-deficient mice through targeted genomic modification (deletion and insertion in Ids gene).
- DNA sequencing to confirm the genetic mutation.
- Assessment of IDS enzyme activity and glycosaminoglycan accumulation.
- Histological and molecular analyses of calvarial bone, including osteoblastogenesis and cell proliferation assays.
- Analysis of osteoblastic marker gene expression (Col1a, Runx2).
Main Results:
- The established Ids-deficient mice exhibited significantly reduced IDS enzyme activity and increased GAG accumulation, consistent with MPS II.
- A distinct enlargement of the calvarial bone was observed in both neonatal and young adult Ids-deficient mice.
- Ids deficiency promoted osteoblastogenesis in the parietal bone, evidenced by enhanced expression of osteoblastic markers Col1a and Runx2.
- Cell proliferation in the parietal bone remained comparable between deficient and wild-type mice, suggesting differentiation, not proliferation, is primarily affected.
Conclusions:
- The novel Ids-deficient mouse model accurately recapitulates key biochemical and skeletal features of MPS II.
- IDS deficiency directly contributes to enhanced calvarial bone development through augmented osteoblast differentiation.
- These findings provide a mechanistic link between IDS deficiency and the enlarged head circumference observed in individuals with MPS II, offering insights for potential therapeutic targets.
