Extracellular matrix disruption is an early event in the pathogenesis of skeletal disease in mucopolysaccharidosis I

Heppner, Jonathan Michael; Zaucke, Frank; Clarke, Lorne A.

doi:10.1016/j.ymgme.2014.09.012

Cited by 36 publications

(25 citation statements)

References 55 publications

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“…Our study demonstrates that the IDUA −/− mice have decreased femur length and are heavier than Wt and IDUA +/− littermates at 16 weeks of age, as has been seen in untreated human patients, and previously in IDUA −/− mice [15], [21] as well as other mouse models of MPS [29], [33], [34]. It is likely that the decreased height observed in Hurler syndrome patients may be attributed to abnormalities in the growth plate caused by GAG accumulation [29], [35], [36]. The growth plates of IDUA −/− femora were shown to have a 4-fold increase in osteoclast activity by tartrate-resistant acid phosphatase histochemistry relative to wildtype femora [21].…”

Section: Discussionmentioning

confidence: 78%

“…A recent study using a different MPS-1 mouse model revealed that changes in extracellular matrix components of the skeleton are a major pathology of the disease which may be independent of GAG accumulation as decreased expression of type I collagen and other cartilaginous proteins occur before the histologic changes are visualized at the growth plate [36]. We further used Raman spectroscopy to evaluate the bone physiochemistry and demonstrated that female IDUA −/− mouse tibias have decreased mineral to matrix ratios and a decreasing trend in mineral to collagen ratios.…”

Section: Discussionmentioning

confidence: 99%

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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

Garcia

Yao

et al. 2015

Molecular Genetics and Metabolism Reports

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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.

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Section: Discussionmentioning

confidence: 78%

Section: Discussionmentioning

confidence: 99%

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

Oestreich

Garcia

Yao

et al. 2015

Molecular Genetics and Metabolism Reports

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“…One key early pathological feature is the disruption of the ECM. [13][14][15] The resulting consequence of this disruption needs to be further understood.…”

Section: Discussionmentioning

confidence: 99%

Free urinary glycosylated hydroxylysine as an indicator of altered collagen degradation in the mucopolysaccharidoses

Patel

Mills

Davison

et al. 2019

J of Inher Metab Disea

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Extracellular matrix (ECM) disruption is known to be an early pathological feature of the Mucopolysaccharidoses (MPS). Collagen is the main component of the ECM and its metabolism could act as a useful indicator of ECM disruption. We have measured the specific collagen breakdown products; urinary free hydroxylated (Lys‐OH) and glycosylated hydroxylysines (Lys‐O‐Gal and Lys‐O‐GalGlc) in MPS patients using a tandem liquid chromatography tandem mass spectrometry assay. A pilot study cohort analysis indicated that concentrations of lysine and Lys‐OH were raised significantly in MPS I (Hurler) disease patients. Lys‐O‐GalGlc was raised in MPS II and MPS VI patients and demonstrated a significant difference between MPS I Hurler and an MPS I Hurler‐Scheie group. Further analysis determined an age association for glycosylated hydroxylysine in control samples similar to that observed for the glycosaminoglycans. Using defined age ranges and treatment naïve patient samples we confirmed an increase in glycosylated hydroxylysines in MPS I and in adult MPS IVA. We also looked at the ratio of Lys‐O‐Gal to Lys‐O‐GalGlc, an indicator of the source of collagen degradation, and noticed a significant change in the ratio for all pediatric MPS I, II, and IV patients, and a small significant increase in adult MPS IV. This indicated that the collagen degradation products were coming from a source other than bone such as cartilage or connective tissue. To see how specific the changes in glycosylated hydroxylysine were to MPS patients we also looked at levels in patients with other inherited metabolic disorders. MPS patients showed a trend towards increased glycosylated hydroxylysines and an elevated ratio compared to other metabolic disorders that included Battens disease, Fabry disease, Pyridoxine‐dependent epilepsy (due to mutations in ALDH7A1), and Niemann Pick C disease.

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“…Spine disease has been characterized in many of the subtypes through methods such as radiography, microcomputed tomography (microCT), and histology. Skeletal disease manifestations, and to some extent spinal disease in MPS I, II, IIIA, IVA, VII, and IX, have all been studied in murine models [68–75]. Murine models have also proven particularly useful for assaying the efficacy of gene therapy and enzyme replacement therapy in alleviating disease symptoms [76–82] as they are biochemically and developmentally well-understood, relatively easy to produce, and can be bred in large, genetically homogenous quantities.…”

Section: Pathophysiology Of Spine Disease In Mpsmentioning

confidence: 99%

“…Murine models have also proven particularly useful for assaying the efficacy of gene therapy and enzyme replacement therapy in alleviating disease symptoms [76–82] as they are biochemically and developmentally well-understood, relatively easy to produce, and can be bred in large, genetically homogenous quantities. Measurements of vertebral bone formation in murine MPS models through bone volume and bone mass measurements as well as bone length and growth plate heights in have shown decreased bone growth, lower hypertrophy in growth plate chondrocytes, and abnormal skeletal development [27, 68, 69, 73–75, 83, 84]. …”

Section: Pathophysiology Of Spine Disease In Mpsmentioning

confidence: 99%

Pathogenesis and treatment of spine disease in the mucopolysaccharidoses

Peck

Casal

Malhotra

et al. 2016

Molecular Genetics and Metabolism

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The mucopolysaccharidoses (MPS) are a family of lysosomal storage disorders characterized by deficient activity of enzymes that degrade glycosaminoglycans (GAGs). Skeletal disease is common in MPS patients, with the severity varying both within and between subtypes. Within the spectrum of skeletal disease, spinal manifestations are particularly prevalent. Developmental and degenerative abnormalities affecting the substructures of the spine can result in compression of the spinal cord and associated neural elements. Resulting neurological complications, including pain and paralysis, significantly reduce patient quality of life and life expectancy. Systemic therapies for MPS such as hematopoietic stem cell transplantation and enzyme replacement therapy have shown limited efficacy for improving spinal manifestations in patients and animal models, and there is therefore a pressing need for new therapeutic approaches that specifically target this debilitating aspect of the disease. In this review, we examine how pathological abnormalities affecting the key substructures of the spine – the discs, vertebrae, odontoid process and dura – contribute to the progression of spinal deformity and symptomatic compression of neural elements. Specifically, we review current understanding of the underlying pathophysiology of spine disease in MPS, how the tissues of the spine respond to current clinical and experimental treatments, and discuss future strategies for improving the efficacy of these treatments.

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Extracellular matrix disruption is an early event in the pathogenesis of skeletal disease in mucopolysaccharidosis I

Cited by 36 publications

References 55 publications

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

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

Free urinary glycosylated hydroxylysine as an indicator of altered collagen degradation in the mucopolysaccharidoses

Pathogenesis and treatment of spine disease in the mucopolysaccharidoses

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