Analysis of bone remodeling in mouse models of mucopolysaccharidosis

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Mucopolysaccharidosis-I (MPS-I) is a lysosomal storage disorder caused by inactivating mutations of IDUA, encoding the matrix-degrading enzyme Iduronidase. Although MPS-I is associated with various abnormalities of skeletal development, growth or modeling, a detailed analysis of the bone remodeling status has not been reported yet. We have previously analyzed a mouse model of mucolipidosis-II, a disease with generalized lysosome dysfunction. Of note, the osteoporotic phenotype of these mice was primarily explained by an unexpected numerical increase of bone-resorbing osteoclasts, thereby raising the question, whether the same applies for other lysosomal storage disorders. To address this question we have analyzed Idua-deficient mice, an established model of MPS-I, and observed high bone mass with reduced osteoclast number. In contrast, we detected osteopenia in a bone biopsy from an individual with MPS-I, yet this patient had been treated by bone marrow transplantation and enzyme replacement therapy. The aim of our project is to obtain a cellular and molecular understanding explaining the impaired skeletal remodeling in MPS-I. In addition, we want to address the question, if and how bone marrow transplantation and/or enzyme replacement therapy influence the bone remodeling status of Idua-deficient mice. Finally, we want to extend our analysis to another MPS model (Arsb-deficient mice) to evaluate the specificity of the MPS-I skeletal phenotype. The collective data obtained in this project should generate a better understanding of bone pathologies in individuals with MPS-I and could provide the basis for improved diagnosis and/or treatment of the disease.