RESUMO
Lack of or dysfunction in osteoclasts result in osteopetrosis, a group of rare but often severe, genetic disorders affecting skeletal tissue. Increase in bone mass results in skeletal malformation and bone marrow failure that may be fatal. Many of the underlying defects have lately been characterized in humans and in animal models of the disease. In humans, these defects often involve mutations in genes expressing proteins involved in the acidification of the osteoclast resorption compartment, a process necessary for proper bone degradation. So far, the only cure for children with severe osteopetrosis is allogeneic hematopoietic stem cell (HSC) transplantation but without a matching donor this form of therapy is far from optimal. The characterization of the genetic defects opens up the possibility for gene replacement therapy as an alternative. Accordingly, HSC-targeted gene therapy in a mouse model of infantile malignant osteopetrosis was recently shown to correct many aspects of the disease.
Assuntos
Osteopetrose/etiologia , Osteopetrose/terapia , Animais , Anidrase Carbônica II/deficiência , Canais de Cloreto/deficiência , Terapia Genética/métodos , Transplante de Células-Tronco Hematopoéticas , Humanos , Lactente , Recém-Nascido , Camundongos , Mutação , Osteoclastos/fisiologia , Osteopetrose/fisiopatologia , Bombas de Próton/deficiênciaAssuntos
Osteoclastos/fisiologia , Osteopetrose/genética , Animais , Reabsorção Óssea/genética , Reabsorção Óssea/fisiopatologia , Anidrases Carbônicas/deficiência , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Canais de Cloreto/genética , Canais de Cloreto/metabolismo , Modelos Animais de Doenças , Genótipo , Humanos , Fator Estimulador de Colônias de Macrófagos/metabolismo , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Camundongos , Mutação , Osteopetrose/fisiopatologia , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Bombas de Próton/deficiência , Bombas de Próton/metabolismo , Ligante RANK , Receptor Ativador de Fator Nuclear kappa-B , Transativadores/genética , Transativadores/metabolismoRESUMO
Tubulointerstitial involvement is well recognized in systemic lupus erythematosus. The tubular dysfunction is usually latent and usually presents after diagnosis of systemic lupus erythematosus. We report a case presenting that she is well previously and initially diagnosed as periodic paralysis of hypokalemia at emergency room and final diagnosis is systemic lupus erythematosus with H+-ATPase pump defect of distal type renal tubular acidosis. Kidney biopsy showed lupus nephritis classified as mesangial proliferative glomerulonephritis WHO class II B. Her renal tubular acidosis was subsided after steroid therapy was administered.
Assuntos
Acidose Tubular Renal/metabolismo , Lúpus Eritematoso Sistêmico/diagnóstico , Bombas de Próton/deficiência , ATPases Translocadoras de Prótons/metabolismo , Adulto , Diagnóstico Diferencial , Feminino , Humanos , Hipopotassemia/diagnóstico , Lúpus Eritematoso Sistêmico/complicações , Nefrite Lúpica/diagnósticoRESUMO
Solubilization of bone mineral by osteoclasts depends on the formation of an acidic extracellular compartment through the action of a V-proton pump that has not yet been characterized at the molecular level. We previously cloned a gene (Atp6i, for V-proton pump, H+ transporting (vacuolar proton pump) member I) encoding a putative osteoclast-specific proton pump subunit, termed OC-116kD (ref. 4). Here we show that targeted disruption of Atp6i in mice results in severe osteopetrosis. Atp6i-/- osteoclast-like cells (OCLs) lose the function of extracellular acidification, but retain intracellular lysosomal proton pump activity. The pH in Atp6i-/- liver lysosomes and proton transport in microsomes of Atp6i-/- kidney are identical to that in wild-type mice. Atp6i-/- mice exhibit a normal acid-base balance in blood and urine. Our results demonstrate that Atp6i is unique and necessary for osteoclast-mediated extracellular acidification.