Mucopolysaccharidosis in a Cat with Arylsulfatase B Deficiency: A Model of Maroteaux-Lamy Syndrome

Jezyk, Peter F.; Haskins, Mark E.; Patterson, Donald F.; Mellman, William J.; Greenstein, Michael

doi:10.1126/science.144321

Cited by 109 publications

(66 citation statements)

References 18 publications

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“…Several naturally occurring MPS animal models exist, [15][16][17][18] providing an excellent source of materials to study this important disease mechanism. The data presented, along with our previous studies, 2,3 show that a central consequence of GAG storage in MPS animals is inflammation.…”

Section: Discussionmentioning

confidence: 99%

Mechanism of Glycosaminoglycan-Mediated Bone and Joint Disease

Simonaro

D’Angelo

et al. 2008

The American Journal of Pathology

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185

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We have previously shown that glycosaminoglycan (GAG) storage in animal models of the mucopolysaccharidoses (MPS) leads to inflammation and apoptosis within cartilage. We have now extended these findings to synovial tissue and further explored the mechanism underlying GAG-mediated disease. Analysis of MPS rats, cats, and/or dogs revealed that MPS synovial fibroblasts and fluid displayed elevated expression of numerous inflammatory molecules, including several proteins important for lipopolysaccharide signaling (eg, Toll-like receptor 4 and lipoprotein-binding protein). The expression of tumor necrosis factor, in particular, was elevated up to 50-fold, leading to up-regulation of the osteoclast survival factor, receptor activator of nuclear factor-B ligand, and the appearance of multinucleated osteoclast-like cells in the MPS bone marrow. Treatment of normal synovial fibroblasts with GAGs also led to production of the prosurvival lipid sphingosine-1-phosphate, resulting in enhanced cell proliferation, consistent with the hyperplastic synovial tissue observed in MPS patients. In contrast, GAG treatment of normal chondrocytes led to production of the proapoptotic lipid ceramide, confirming the enhanced cell death we had previously observed in MPS cartilage. These findings have important implications for the pathogenesis and treatment of MPS and have further defined the mechanism of GAG-stimulated disease. (Am J Pathol

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Section: Discussionmentioning

confidence: 99%

Mechanism of Glycosaminoglycan-Mediated Bone and Joint Disease

Simonaro

D’Angelo

et al. 2008

The American Journal of Pathology

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185

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“…The MPS VI cat and rat models, and MPS VII dog model have been previously described (2)(3)(4). Affected and control animals were raised under National Institutes of Health and USDA guidelines for the care and use of animals in research.…”

Section: Animalsmentioning

confidence: 99%

“…There are numerous MPS animal models available for study, either naturally occurring or generated through targeted disruption of the corresponding mouse gene (e.g., [2][3][4][5]. These animal models have biochemical and pathologic features that are similar to their human counterparts, and their availability has facilitated the evaluation of various therapeutic approaches and a better understanding of the disease pathogenesis.…”

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confidence: 99%

Joint and Bone Disease in Mucopolysaccharidoses VI and VII: Identification of New Therapeutic Targets and BioMarkers Using Animal Models

et al. 2005

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The mucopolysaccharidoses (MPS) are inherited metabolic disorders resulting from the defective catabolism of glycosaminoglycans. In this report, we find that the stimulation of MPS connective tissue cells by the inflammatory cytokines causes enhanced secretion of several matrix-degrading metalloproteinases (MMPs). In addition, expression of tissue inhibitor of metalloproteinase-1 was elevated, consistent with the enhanced MMP activity. These findings were not restricted to one particular MPS disorder or species, and are consistent with previous observations in animal models with chemically induced arthritis. Bromodeoxyuridine incorporation studies also revealed that MPS chondrocytes proliferated up to 5-fold faster than normal chondrocytes, and released elevated levels of transforming growth factor-beta, presumably to counteract the marked chondrocyte apoptosis and matrix degradation associated with MMP expression. Despite this compensatory mechanism, studies of endochondral ossification revealed a reduction in chondrodifferentiation in the growth plates. Thus, although MPS chondrocytes grew faster, most of the newly formed cells were immature and could not mineralize into bone. Our studies suggest that altered MMP expression, most likely stimulated by inflammatory cytokines and nitric oxide, is an important feature of the MPS disorders. These data also identify several proinflammatory cytokines, nitric oxide, and MMPs as novel therapeutic targets and/or biomarkers of MPS joint and bone disease. This information should aid in the evaluation of existing therapies for these disorders, such as enzyme replacement therapy and bone marrow transplantation, and may lead to the development of new therapeutic approaches. The accumulation of partially degraded glycosaminoglycans (GAGs) in late endosomes and lysosomes of connective tissue cells is characteristic of a family of heritable lysosomal storage diseases known as the mucopolysaccharidoses (MPS) (1). The MPS family consists of 12 chronic and progressive syndromes, each with a specific enzyme deficiency leading to a characteristic pattern of accumulating GAGs within lysosomes. Among the different MPS disorders, there are several clinical characteristics present in most affected individuals. These include anterior hypoplasia of lumbar vertebrae, enlarged diaphyses of the long bones, underdeveloped epiphyseal centers, marked dwarfism, degenerative joint disease, dysostosis multiplex, facial dysmorphia, organomegaly, corneal clouding, and in most syndromes mental retardation (1). Cartilage is a major site of pathology in these diseases, leading to painful joints, poor joint mobility, poor bone growth, and an abnormal larynx and trachea producing breathing abnormalities often requiring tracheotomies.

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“…This disease has been described in humans, dogs, mice, and a single cat from Switzerland. [2][3][4][5][6][7][8]12 Canine and murine animal models have been used to investigate enzyme replacement, bone marrow transplantation, and gene therapy as possible treatments of the disease. 1,[9][10][11] Here, we describe the clinical and postmortem findings of MPS VII in a cat.…”

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confidence: 99%

Mucopolysaccharidosis VII in a Cat

Schultheiss¹,

Gardner²,

Owens³

et al. 2000

Vet Pathol

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Abstract. Mucopolysaccharidosis VII was diagnosed in a domestic shorthair cat from California. The cat was small and had multiple abnormalities, including a small body disproportionate to the size of the skull, angular deformities of the ribs, abnormally short forelimbs, luxating patellas, generalized epiphyseal dysplasia involving the vertebrae and long bones, cuboidal vertebrae, pectus excavatum, subluxation of both hips, osteosclerosis of the tentorium cerebelli and left petrous temporal bone, tracheal hypoplasia, and corneal clouding. ␤-Glucuronidase activity was markedly decreased in peripheral blood leukocytes. The cat died at 21 months of age, and a complete necropsy was performed. Tissues were examined by light and transmission electron microscopy. Large clear, round vacuoles representing distended lysosomes were present in many epithelial and connective tissue cells, including fibrocytes, chondrocytes, smooth muscle cells, hepatocytes, astrocytes, and macrophages.

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Mucopolysaccharidosis in a Cat with Arylsulfatase B Deficiency: A Model of Maroteaux-Lamy Syndrome

Cited by 109 publications

References 18 publications

Mechanism of Glycosaminoglycan-Mediated Bone and Joint Disease

Mechanism of Glycosaminoglycan-Mediated Bone and Joint Disease

Joint and Bone Disease in Mucopolysaccharidoses VI and VII: Identification of New Therapeutic Targets and BioMarkers Using Animal Models

Mucopolysaccharidosis VII in a Cat

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