RESUMO
Mutations in the 2Cl(-)/1H(+)-exchanger ClC-7 impair osteoclast function and cause different types of osteoclast-rich osteopetrosis. However, it is unknown to what extent ClC-7 function has to be reduced to become rate-limiting for bone resorption. In osteoclasts from osteopetrosis patients expression of the mutated ClC-7 protein did not correlate with disease severity and resorption impairment. Therefore, a series of transgenic mice expressing ClC-7 in osteoclasts at different levels was generated. Crossing of these mice with Clcn7(-/-) mutants rescued the osteopetrotic phenotype to variable degrees. One resulting double transgenic line mimicked human autosomal dominant osteopetrosis. The trabecular bone of these mice showed a reduction of osteoblast numbers, osteoid, and osteoblast marker gene expression indicative of reduced osteoblast function. In osteoclasts from these mutants ClC-7 expression levels were 20 to 30% of wildtype levels. These reduced levels not only impaired resorptive activity, but also increased numbers, size and nucleus numbers of osteoclasts differentiated in vitro. Although ClC-7 was expressed in the stomach and PTH levels were high in Clcn7(-/-) mutants loss of ClC-7 did not entail a relevant elevation of gastric pH. In conclusion, we show that in our model a reduction of ClC-7 function by approximately 70% is sufficient to increase bone mass, but does not necessarily enhance bone formation. ClC-7 does not appear to be crucially involved in gastric acid secretion, which explains the absence of an osteopetrorickets phenotype in CLCN7-related osteopetrosis.
Assuntos
Remodelação Óssea , Canais de Cloreto/genética , Ácido Gástrico/metabolismo , Animais , Reabsorção Óssea/complicações , Reabsorção Óssea/genética , Reabsorção Óssea/patologia , Reabsorção Óssea/fisiopatologia , Cálcio/metabolismo , Contagem de Células , Diferenciação Celular/genética , Fusão Celular , Canais de Cloreto/deficiência , Canais de Cloreto/metabolismo , Genes Dominantes , Genes Recessivos , Humanos , Concentração de Íons de Hidrogênio , Camundongos , Camundongos Transgênicos , Osteoblastos/metabolismo , Osteoblastos/patologia , Osteoclastos/metabolismo , Osteoclastos/patologia , Osteogênese/genética , Osteopetrose/complicações , Osteopetrose/genética , Osteopetrose/patologia , Osteopetrose/fisiopatologia , FenótipoRESUMO
Se presentan 3 casos de Insulinoma, vistos en nuestro Servicio durante el año 1995. Dado lo raro de esta patología se decide hacer una breve revisión del tema poniendo especial énfasis en lo que a diagnóstico bioquímico y topográfico respecta. Se discute cuál puede ser el mejor procedimiento para esto último y si realmente se justifican los esfuerzos. Se destaca el rol de la ecotomografía intraoperatoria para realizar resecciones precisas; no hubo morbimortalidad en la serie y los controles alejados han demostrado normoglicemia
