Enhanced differentiation of osteoclasts from mononuclear precursors in patients with Gaucher disease.
Blood Cells Mol Dis
; 51(3): 185-94, 2013 Oct.
Article
em En
| MEDLINE
| ID: mdl-23707505
ABSTRACT
Gaucher disease (GD) is an autosomal recessive disorder caused by deficiency of ß-glucocerebrosidase. Storage of glucosylceramide in reticuloendothelial cells results in multiorgan pathology including bone disease. Established skeletal disease may remain problematic despite Gaucher-specific treatment. Both osteopenia and osteonecrosis have been described but the underlying pathophysiology, in particular the role of monocyte-derived osteoclasts is not well defined. The objective of this study was to explore the effect of glucocerebrosidase deficiency, inhibition and replacement on osteoclast development and function. In cultures derived from GD patients, or where GBA was chemically inhibited multinucleate giant cells expressing markers of osteoclast differentiation occurred earlier and in greater numbers compared to normal controls and the functional capacity of osteoclasts for bone resorption was enhanced. Increases in osteoclast number and activity correlated with radiological markers of active bone disease. Abnormalities were reversed by addition of specific therapies and were attenuated by co-culture with cells derived from healthy controls (HCs). Numbers of osteoblast lineage cells in the peripheral blood were mismatched to osteoclast precursors indicating uncoupling of osteoblast-osteoclast regulation which may further impact on bone remodelling. Elucidation of the underlying mechanisms of these changes will suggest rational therapies for the most disabling aspect of this condition.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Osteoclastos
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Leucócitos Mononucleares
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Diferenciação Celular
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Doença de Gaucher
Limite:
Adult
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Aged
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Aged80
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
Blood Cells Mol Dis
Assunto da revista:
HEMATOLOGIA
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
Reino Unido