Altered bone structure in Niemann-Pick Type C1 mice, especially in females

Niemann-Pick type C disease (NPC) is a rare lysosomal storage disorder belonging to the group of sphingolipidoses and is caused by a genetic defect affecting cholesterol trafficking. Since other sphingolipidoses with lipid accumulations show disrupt bone, this study investigated bone structure in an Npc1 mouse model and assessed whether pharmacological treatments (miglustat, 2-hydroxypropyl-β-cyclodextrin [HPßCD], and combination therapy including allopregnanolone) affected it. Femora from Npc1^-/^- mice of postnatal day (P) 65 were analysed using histology, histomorphometry and micro-CT. Additionally, femur and vertebral bodies of mice from P30, P40 and P65 were examined by real-time RT-PCR. Histomorphometric findings revealed a significantly reduced relative bone area in female Npc1^-/^- mice compared to wild-type mice. Micro-CT analysis confirmed this by demonstrating deteriorated trabecular bone structures in female Npc1^-/^- mice. Following treatment, particularly with combination therapy, an improvement in the bone microarchitecture was observed. Differences relative to wild-type mice were often no longer detectable. Furthermore, there was some evidence that combi therapy also increased the relative numbers of osteoblasts and osteoclasts. Since real-time RT-PCR indicated low expression of osteoclast and osteocyte targets cathepsin K and connexin-43, respectively, a stimulation of bone cells might decelerate postnatal disease progression. While at P30, sphingosine-kinase-1 (SphK1) expression was increased in female Npc1^-/^- mice, it decreased in femur at P40 and in vertebral bodies at P65. This decline was not measured in male Npc1^-/^- mice revealing a sex-dependent decline of bone structures in female Npc1^-/^- mice. Overall, disease-modifying treatment regimens targeting lipid storage improved bone microarchitecture in a sex-dependent manner.