Characterization Of The Skeletal Phenotype In Idua-W392X Knock-In Mice: Bone Metabolism Biomarkers
Mucopolysaccharidosis Type I (MPS I, Hurlers Syndrome) is a lysosomal storage disease caused by a deficiency of alpha-L-iduronidase (IDUA). IDUA catalyzes the degradation of the two glycosaminoglycans (GAGs); heparin sulfate (HS) and demantan sulfate (DS). The accumulation of HS and DS makes MPS I progressive with inevitable degeneration of multiple organ systems. Accumulated excess of GAGs on the skeletal system causes dysostosis multiplex, atlantoaxial instability, thoracolumbar kyphosis, genu valgum, acetabular dysplasia, and short stature. Skeletal biomarkers of bone formation and bone resorption were compared in wild-type, heterozygous, and IDUAW392X mice. To investigate osteoblast activity, levels of the bone formation marker Procollagen type I N-terminal propeptide (PINP) were evaluated. To investigate osteoclast activity, levels of the bone resorption biomarker Tartrate-resistant acid phosphatase (TRAP5b) were evaluated. Potential differences in serum PINP or serum TRAP5b concentrations could contribute to the increased cortical thickness and increased bone marrow width seen in the skeletal phenotype previously identified in mice with IDUA deficiency. Lastly to further investigate bone metabolism, transcription of six biomarkers were quantified: collagen (I), RANKL, OPG, TNFα, and CSF-1 isolated from tibiae of wild type, heterozygous, and DUAW392X mice. No significant differences were found between the genotypes for PINP, TRAP5b, and transcription levels of type I collagen. Lower transcriptional levels were found for RANKL, OPG, TNFα and CSF-1 for IDUA deficient mice compared to wild-type mice.
mucopolysaccardosis, Hurlers syndrome, lysosomal storage disorder, α-L-iduronidase bone remodeling, bone resorption, bone formation, PINP, TRAP5b, Medical Molecular Biology
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