RESUMO
Adipokine adiponectin (APN) has been recently reported to play a role in regulating bone mineral density (BMD). To explore the mechanism by which APN affects BMD, we investigated BMD and biomechanical strength properties of the femur and vertebra in sham-operated (Sham) and ovariectomized (OVX) APN knockout (KO) mice as compared to their operated wild-type (WT) littermates. The results show that APN deficiency has no effect on BMD but induces increased ALP activity and osteoclast cell number. While OVX indeed leads to significant bone loss in both femora and vertebras of WT mice with comparable osteogenic activity and a significant increase in osteoclast cell number when compared to that of sham control. However, no differences in BMD, ALP activity and osteoclast cell number were found between Sham and OVX mice deficient for APN. Further studies using bone marrow derived mesenchymal stem cells (MSCs) demonstrate an enhanced osteogenic differentiation and extracellular matrix calcification in APN KO mice. The possible mechanism for APN deletion induced acceleration of osteogenesis could involve increased proliferation of MSCs and higher expression of Runx2 and Osterix genes. These findings indicate that APN deficiency can protect against OVX-induced osteoporosis in mice, suggesting a potential role of APN in regulating the balance of bone formation and bone resorption, especially in the development of post-menopausal osteoporosis.
Assuntos
Adiponectina/deficiência , Densidade Óssea/fisiologia , Osteoporose/fisiopatologia , Ovariectomia , Absorciometria de Fóton , Adiponectina/genética , Fosfatase Alcalina/genética , Fosfatase Alcalina/metabolismo , Animais , Densidade Óssea/genética , Células da Medula Óssea/citologia , Células da Medula Óssea/metabolismo , Cálcio/metabolismo , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Proliferação de Células , Células Cultivadas , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Feminino , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Osteoblastos/citologia , Osteoblastos/metabolismo , Osteoclastos/citologia , Osteoclastos/metabolismo , Osteogênese/genética , Osteoporose/genética , Osteoporose/prevenção & controle , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Transcrição Sp7 , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
The osteoblast-derived paracrine factor osteoprotegerin (OPG) is considered to play a key role in inhibition of osteoclast formation and activity. Recently, raloxifene, a nonsteroidal benzothiophene, was found to exert anti-resorptive effects via modulating OPG expression in osteoblasts. To explore whether raloxifene regulates bone metabolism via an OPG-dependant pathway in vivo, we investigated the effects of raloxifene on bone loss in Opg-deficient mice. The results show that bone mineral density and bone strength are increased in mice deficient for Opg after treatment with raloxifene for 30 days. Histomorphometric analysis shows that raloxifene can increase bone trabecular area and decrease the number of osteoclasts in Opg (-/-) mice. Moreover, raloxifene reduces Rankl transcription and serum level of Rankl, which is dramatically increased in Opg knockout mice. These results suggest that raloxifene-induced inhibition of bone resorption may be independent of Opg pathway in mice.
Assuntos
Conservadores da Densidade Óssea/farmacologia , Conservadores da Densidade Óssea/uso terapêutico , Reabsorção Óssea/prevenção & controle , Osso e Ossos/efeitos dos fármacos , Osteoprotegerina/metabolismo , Cloridrato de Raloxifeno/farmacologia , Cloridrato de Raloxifeno/uso terapêutico , Animais , Densidade Óssea/efeitos dos fármacos , Reabsorção Óssea/sangue , Reabsorção Óssea/metabolismo , Reabsorção Óssea/patologia , Osso e Ossos/química , Osso e Ossos/patologia , Contagem de Células , Módulo de Elasticidade , Feminino , Fêmur/química , Fêmur/efeitos dos fármacos , Fêmur/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Vértebras Lombares/química , Vértebras Lombares/efeitos dos fármacos , Vértebras Lombares/patologia , Fenômenos Mecânicos , Camundongos , Camundongos Knockout , Osteoclastos/efeitos dos fármacos , Osteoclastos/patologia , Osteoprotegerina/sangue , Osteoprotegerina/genética , Ligante RANK/sangue , Ligante RANK/genética , Ligante RANK/metabolismo , RNA Mensageiro/metabolismo , Distribuição AleatóriaRESUMO
Palladin is an actin cytoskeleton-associated protein which is crucial for cell morphogenesis and motility. Previous studies have shown that palladin is localized to the axonal growth cone in neurons and may play an important role in axonal extension. Previously, we have generated palladin knockout mice which display cranial neural tube closure defect and embryonic lethality before embryonic day 15.5 (E15.5). To further study the role of palladin in the developing nervous system, we examined the innervation of palladin-deficient mouse embryos since the 200 kd, 140 kd, 90-92 kd and 50 kd palladin isoforms were undetectable in the mutant mouse embryo brain. Contrary to the results of previous studies, we found no inhibition of the axonal extension in palladin-deficient mouse embryos. The cortical neurons derived from palladin-deficient mice also showed no significant difference in neurite outgrowth as compared with those from wild-type mice. Moreover, no difference was found in neurite outgrowth of neural stem cell derived-neurons between palladin-deficient mice and wild-type mice. In conclusion, these results suggest that palladin is dispensable for normal neurite outgrowth in mice.