Analysis of bone remodeling in mouse models of mucopolysaccharidosis

粘多糖症-I(MPS-I)是一种由IDUA基因突变失活引起的溶酶体储存障碍，编码基质降解酶艾杜糖苷酶。尽管MPS-I与骨骼发育、生长或造型的各种异常有关，但关于骨重建状态的详细分析尚未见报道。我们之前已经分析了一种粘脂病-II的小鼠模型，这是一种具有全身性溶酶体功能障碍的疾病。值得注意的是，这些小鼠的骨质疏松表型主要是通过骨吸收破骨细胞的意外数量增加来解释的，因此提出了一个问题，即其他溶酶体储存障碍是否也是如此。为了解决这个问题，我们分析了IDUA缺乏的小鼠，一个建立的MPS-I模型，观察到破骨细胞数量减少的高骨量。相反，我们在一名患有MPS-I的患者的骨活检中检测到骨量减少，但这名患者已经接受了骨髓移植和酶替代治疗。我们项目的目的是为了获得对MPS-I受损骨骼重塑的细胞和分子方面的理解。此外，我们希望解决这个问题，即骨髓移植和/或酶替代疗法是否以及如何影响IDUA缺陷小鼠的骨重建状态。最后，我们希望将我们的分析扩展到另一个MPS模型(ARSB缺陷小鼠)，以评估MPS-I骨骼表型的特异性。在这个项目中获得的集体数据应该可以更好地了解患有MPS-I的个体的骨骼病理，并可以为改进疾病的诊断和/或治疗提供基础。

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.