RESUMO
We report that oxytocin (OT), a primitive neurohypophyseal hormone, hitherto thought solely to modulate lactation and social bonding, is a direct regulator of bone mass. Deletion of OT or the OT receptor (Oxtr) in male or female mice causes osteoporosis resulting from reduced bone formation. Consistent with low bone formation, OT stimulates the differentiation of osteoblasts to a mineralizing phenotype by causing the up-regulation of BMP-2, which in turn controls Schnurri-2 and 3, Osterix, and ATF-4 expression. In contrast, OT has dual effects on the osteoclast. It stimulates osteoclast formation both directly, by activating NF-kappaB and MAP kinase signaling, and indirectly through the up-regulation of RANK-L. On the other hand, OT inhibits bone resorption by mature osteoclasts by triggering cytosolic Ca(2+) release and NO synthesis. Together, the complementary genetic and pharmacologic approaches reveal OT as a novel anabolic regulator of bone mass, with potential implications for osteoporosis therapy.
Assuntos
Osso e Ossos/metabolismo , Ocitocina/metabolismo , Animais , Osso e Ossos/citologia , Osso e Ossos/efeitos dos fármacos , Cálcio/metabolismo , Camundongos , Camundongos Knockout , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Osteogênese/efeitos dos fármacos , Ocitocina/deficiência , Ocitocina/genética , Ocitocina/farmacologiaRESUMO
During space flight, severe losses of bone mass are observed. Both bone formation and resorption are probably involved, but their relative importance remains unclear. The purpose of this research is to understand the role of osteoclasts and their precursors in microgravity-induced bone loss. Three experiments on isolated osteoclasts (OCs) and on their precursors, OSTEO, OCLAST, and PITS, were launched in the FOTON-M3 mission. The OSTEO experiment was conducted for 10 d in microgravity within bioreactors with a perfusion system, where the differentiation of precursors, cultured on a synthetic 3-dimensional bonelike biomaterial, skelite, toward mature OCs was assessed. In OCLAST and in PITS experiments, differentiated OCs were cultured on devitalized bovine bone slices for 4 d in microgravity. All of the experiments were replicated on ground in the same bioreactors, and OCLAST also had an inflight centrifuge as a control. Gene expression in microgravity, compared with ground controls, demonstrated a severalfold increase in genes involved in osteoclast maturation and activity. Increased bone resorption, proved by an increased amount of collagen telopeptides released VS ground and centrifuge control, was also found. These results indicate for the first time osteoclasts and their precursors as direct targets for microgravity and mechanical forces.
Assuntos
Reabsorção Óssea/etiologia , Osteoclastos/patologia , Osteoclastos/fisiologia , Voo Espacial , Ausência de Peso/efeitos adversos , Animais , Sequência de Bases , Reatores Biológicos , Reabsorção Óssea/genética , Reabsorção Óssea/patologia , Reabsorção Óssea/fisiopatologia , Bovinos , Diferenciação Celular , Células Cultivadas , DNA Complementar/genética , Expressão Gênica , Técnicas In Vitro , Camundongos , Células-Tronco/patologia , Células-Tronco/fisiologia , Simulação de Ausência de Peso/efeitos adversosRESUMO
A study is presented on the expression and activity of complex I, as well as of other complexes of the respiratory chain, in the course of brain development and inherited encephalopathies. Investigations on mouse hippocampal cells show that differentiation of these cells both in vivo and in cell cultures is associated with the expression of a functional complex I, whose activity markedly increases with respect to that of complexes III and IV. Data are presented on genetic defects of complex I in six children with inborn encephalopathy associated with isolated deficiency of the complex. Mutations have been identified in nuclear and mitochondrial genes coding for subunits of the complex. Different mutations were found in the nuclear NDUFS4 gene coding for the 18 kD (IP, AQDQ) subunit of complex I. All the NDUFS4 mutations resulted in impairment of the assembly of a functional complex. The observations presented provide evidence showing a critical role of complex I in differentiation and functional activity of brain cells.
Assuntos
Mapeamento Cromossômico , Complexo I de Transporte de Elétrons/genética , Hipocampo/enzimologia , Mutação , Animais , Diferenciação Celular , DNA Complementar/genética , Modelos Animais de Doenças , Hipocampo/citologia , Humanos , Camundongos , Encefalomiopatias Mitocondriais/enzimologia , Encefalomiopatias Mitocondriais/genética , Neurônios/citologia , Neurônios/enzimologiaRESUMO
Presented is a study of the impact on the structure and function of human complex I of three different homozygous mutations in the NDUFS4 gene coding for the 18-kDa subunit of respiratory complex I, inherited by autosomal recessive mode in three children affected by a fatal neurological Leigh-like syndrome. The mutations consisted, respectively, of a AAGTC duplication at position 466-470 of the coding sequence, a single base deletion at position 289/290, and a G44A nonsense mutation in the first exon of the gene. All three mutations were found to be associated with a defect of the assembly of a functional complex in the inner mitochondrial membrane. In all the mutations, in addition to destruction of the carboxyl-terminal segment of the 18-kDa subunit, the amino-terminal segment of the protein was also missing. In the mutation that was expected to produce a truncated subunit, the disappearance of the protein was associated with an almost complete disappearance of the NDUFS4 transcript. These observations show the essential role of the NDUFS4 gene in the structure and function of complex I and give insight into the pathogenic mechanism of NDUFS4 gene mutations in a severe defect of complex I.