Characterization of the MPS I-H knock-in mouse reveals increased femoral biomechanical integrity with compromised material strength and altered bone geometry
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 glycosaminogly...
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| Format: | Article |
| Language: | English |
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Elsevier
2015-12-01
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| Series: | Molecular Genetics and Metabolism Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2214426915300288 |
| _version_ | 1819092038121947136 |
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| author | Arin K. Oestreich Mekka R. Garcia Xiaomei Yao Ferris M. Pfeiffer Sabah Nobakhti Sandra J. Shefelbine Yong Wang Amanda C. Brodeur Charlotte L. Phillips |
| author_facet | Arin K. Oestreich Mekka R. Garcia Xiaomei Yao Ferris M. Pfeiffer Sabah Nobakhti Sandra J. Shefelbine Yong Wang Amanda C. Brodeur Charlotte L. Phillips |
| author_sort | Arin K. Oestreich |
| collection | DOAJ |
| description | 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 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. μCT 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 μCT, 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. |
| first_indexed | 2024-12-21T22:49:15Z |
| format | Article |
| id | doaj.art-6ad02d00d4274b6b919708fdf62ba78d |
| institution | Directory Open Access Journal |
| issn | 2214-4269 |
| language | English |
| last_indexed | 2024-12-21T22:49:15Z |
| publishDate | 2015-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Genetics and Metabolism Reports |
| spelling | doaj.art-6ad02d00d4274b6b919708fdf62ba78d2022-12-21T18:47:36ZengElsevierMolecular Genetics and Metabolism Reports2214-42692015-12-015C31110.1016/j.ymgmr.2015.08.004Characterization of the MPS I-H knock-in mouse reveals increased femoral biomechanical integrity with compromised material strength and altered bone geometryArin K. Oestreich0Mekka R. Garcia1Xiaomei Yao2Ferris M. Pfeiffer3Sabah Nobakhti4Sandra J. Shefelbine5Yong Wang6Amanda C. Brodeur7Charlotte L. Phillips8Department of Biological Sciences, University of Missouri, Columbia, MO 65211, United StatesDepartment of Biochemistry, University of Missouri, Columbia, MO 65211, United StatesDepartment of Oral and Craniofacial Sciences, School of Dentistry, University of Missouri-Kansas City, Kansas City, MO 64108, United StatesDepartment of Orthopaedic Surgery and Bioengineering, University of Missouri, Columbia, MO 65211, United StatesDepartment of Mechanical and Industrial Engineering, Northeastern University, Boston, MA 02115, United StatesDepartment of Mechanical and Industrial Engineering, Northeastern University, Boston, MA 02115, United StatesDepartment of Oral and Craniofacial Sciences, School of Dentistry, University of Missouri-Kansas City, Kansas City, MO 64108, United StatesDepartment of Biomedical Sciences, Missouri State University, Springfield, MO 65804, United StatesDepartment of Biochemistry, University of Missouri, Columbia, MO 65211, United StatesMucopolysaccharidosis 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 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. μCT 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 μCT, 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.http://www.sciencedirect.com/science/article/pii/S2214426915300288Bone biomechanicsRaman spectroscopyMucopolysaccharidosis type IIdua-W392Xα-L-iduronidase |
| spellingShingle | Arin K. Oestreich Mekka R. Garcia Xiaomei Yao Ferris M. Pfeiffer Sabah Nobakhti Sandra J. Shefelbine Yong Wang Amanda C. Brodeur Charlotte L. Phillips Characterization of the MPS I-H knock-in mouse reveals increased femoral biomechanical integrity with compromised material strength and altered bone geometry Molecular Genetics and Metabolism Reports Bone biomechanics Raman spectroscopy Mucopolysaccharidosis type I Idua-W392X α-L-iduronidase |
| title | Characterization of the MPS I-H knock-in mouse reveals increased femoral biomechanical integrity with compromised material strength and altered bone geometry |
| title_full | Characterization of the MPS I-H knock-in mouse reveals increased femoral biomechanical integrity with compromised material strength and altered bone geometry |
| title_fullStr | Characterization of the MPS I-H knock-in mouse reveals increased femoral biomechanical integrity with compromised material strength and altered bone geometry |
| title_full_unstemmed | Characterization of the MPS I-H knock-in mouse reveals increased femoral biomechanical integrity with compromised material strength and altered bone geometry |
| title_short | Characterization of the MPS I-H knock-in mouse reveals increased femoral biomechanical integrity with compromised material strength and altered bone geometry |
| title_sort | characterization of the mps i h knock in mouse reveals increased femoral biomechanical integrity with compromised material strength and altered bone geometry |
| topic | Bone biomechanics Raman spectroscopy Mucopolysaccharidosis type I Idua-W392X α-L-iduronidase |
| url | http://www.sciencedirect.com/science/article/pii/S2214426915300288 |
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