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Characterization of the MPS I-H knock-in mouse reveals increased femoral biomechanical integrity with compromised material strength and altered bone geometry.

ABSTRACT: Mucopolysaccharidosis type I (MPS I), is an autosomal recessive lysosomal storage disorder caused by a deficiency in the ?-L-iduronidase enzyme, resulting in decreased enzymatic activity and accumulation of glycosaminoglycans. The disorder phenotypically manifests with increased urine glycosaminoglycan excretion, facial dysmorphology, neuropathology, cardiac manifestations, and bone deformities. While the development of new treatment strategies have shown promise in attenuating many symptoms associated with the disorder, the bone phenotype remains unresponsive. The aim of this study was to investigate and further characterize the skeletal manifestations of the Idua-W392X knock-in mouse model, which carries a nonsense mutation corresponding to the IDUA-W402X mutation found in Hurler syndrome (MPS I-H) patients. ?CT analysis of the microarchitecture demonstrated increased cortical thickness, trabecular number, and trabecular connectivity along with decreased trabecular separation in the tibiae of female homozygous Idua-W392X knock-in (IDUA-/-) mice, and increased cortical thickness in male IDUA-/- tibiae. Cortical density, as determined by ?CT, and bone mineral density distribution, as determined by quantitative backscattered microscopy, were equivalent in IDUA-/- and wildtype (Wt) bone. However, tibial porosity was increased in IDUA-/- cortical bone. Raman spectroscopy results indicated that tibiae from female IDUA-/- had decreased phosphate to matrix ratios and increased carbonate to phosphate ratios compared to Wt female tibiae, whereas these ratios remained equivalent in male IDUA-/- and Wt tibiae. Femora demonstrated altered geometry and upon torsional loading to failure analysis, female IDUA-/- mouse femora exhibited increased torsional ultimate strength, with a decrease in material strength relative to Wt littermates. Taken together, these findings suggest that the IDUA-/- mutation results in increased bone torsional strength by altering the overall bone geometry and the microarchitecture which may be a compensatory response to increased porosity, reduced bone tensile strength and altered physiochemical composition.

SUBMITTER: Oestreich AK

PROVIDER: S-EPMC5471398 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Characterization of the MPS I-H knock-in mouse reveals increased femoral biomechanical integrity with compromised material strength and altered bone geometry.

Oestreich Arin K AK Garcia Mekka R MR Yao Xiaomei X Pfeiffer Ferris M FM Nobakhti Sabah S Shefelbine Sandra J SJ Wang Yong Y Brodeur Amanda C AC Phillips Charlotte L CL

Molecular genetics and metabolism reports 20150907

Mucopolysaccharidosis type I (MPS I), is an autosomal recessive lysosomal storage disorder caused by a deficiency in the α-L-iduronidase enzyme, resulting in decreased enzymatic activity and accumulation of glycosaminoglycans. The disorder phenotypically manifests with increased urine glycosaminoglycan excretion, facial dysmorphology, neuropathology, cardiac manifestations, and bone deformities. While the development of new treatment strategies have shown promise in attenuating many symptoms ass ...[more]

PMID: 28649535

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Project description:IntroductionWe have recently reported about a novel technique for the generation of bioartificial vascular grafts based on the use of a compacted fibrin matrix. In this study, we evaluated the effects of a dehydration process on the biomechanical properties of compacted fibrin tubes and whether it allows for their long-term storage.Materials and methodsFibrin was precipitated from fresh frozen plasma by means of cryoprecipitation and simultaneously with a thrombin solution applied in a high-speed rotating casting mold. Subsequent dehydration of the fibrin tubes (29/38) was performed in dry air with a dilator inside the tube to prevent the collapse of the lumen. Dehydrated fibrin tubes were stored for six (n=9) and 12 months (n=10) at room temperature. Comparative analysis was done on initially generated and dehydrated fibrin tubes before and after storage to evaluate the effects of the dehydration process and storage on the biomechanical properties and structure of the tubes.ResultsThirty-eight fibrin tubes were generated by high-speed rotation-molding from 142±3 mg fibrinogen with an inner diameter of 5.8±0.1 mm and a length of 100 mm. A centrifugal force of nearly 900×g compacted applied fibrin, while fluid was pressed out of the matrix and drained from the mold via holes resulting in a 16-fold compaction of the fibrin matrix. Dehydration was characterized by shrinkage of the tubes to a diameter of 3.2±0.2 mm, while the length remained at 100 mm equivalent to a further two-fold compaction. The biomechanical strength of the dehydrated fibrin tubes significantly increased to values comparable to that of native ovine carotid arteries and maintained during the first 6 months of storage. After 12 months of storage, only five of 10 tubes were intact, and only one showed maintained biomechanical strength.DiscussionCompaction of a fibrin matrix in high-speed rotation-moulding and subsequent dehydration enables for the construction of small-caliber fibrin grafts. Over and above, the dehydration process allows their storage and stockpiling as a prerequisite for clinical use.

Project description:Low serum 25-hydroxy vitamin D (25(OH)D) concentrations are associated with increased hip fracture risk and decreased femoral areal bone mineral density (BMD) among elderly men. Structural dimensions of the proximal femur and volumetric BMD in cortical and trabecular compartments are also associated with hip fracture risk. However, associations of volumetric BMD or structural dimensions with serum 25(OH)D concentrations among older men remain unclear. In a random sample of 1608 men aged ?65 years from the Osteoporotic Fractures in Men Study (MrOS), baseline serum 25(OH)D concentrations were measured by liquid chromatography/mass spectrometry assays. Femoral neck geometry and volumetric BMD derived from quantitative computed tomography included integral, cortical, and trabecular volumetric BMD; cross-sectional area; integral and cortical volume; and cortical volume as a percent of integral volume. We studied 888 men with vitamin D, parathyroid hormone (PTH), femoral neck geometry, and BMD measures. Whole-bone femoral strength and load-strength ratio from finite element (FE) analysis were also available for 356 men from this sample. Multivariable linear regression was used to estimate least square means of each femoral measure within quartiles of 25(OH)D adjusted for age, race, body mass index, height, latitude, and season of blood draw. Tests of linear trend in the means were performed across increasing quartile of serum 25(OH)D levels. Mean cortical volume (p trend?=?0.006) and cortical volume as a percent of integral volume (p trend?<?0.001) increased across increasing quartile of 25(OH)D level. However, overall femoral neck size (area and integral volume) did not vary by 25(OH)D level. Femoral neck volumetric BMD measures increased in a graded manner with higher 25(OH)D levels (p trend?<?0.001). Femoral strength, but not load-strength ratio, increased with increasing 25(OH)D. Adjustment for PTH did not materially change these associations. We conclude that in older men, higher levels of endogenous 25(OH)D may increase whole-bone strength by increasing femoral volumetric BMD and cortical volume.

Dataset Information

Characterization of the MPS I-H knock-in mouse reveals increased femoral biomechanical integrity with compromised material strength and altered bone geometry.

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Characterization of the MPS I-H knock-in mouse reveals increased femoral biomechanical integrity with compromised material strength and altered bone geometry.

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