RESUMO
During osteoporosis bone formation by osteoblasts is reduced and/or bone resorption by osteoclasts is enhanced. Currently, only a few factors have been identified in the regulation of bone integrity by osteoblast-derived osteocytes. In this study, we show that specific disruption of menin, encoded by multiple endocrine neoplasia type 1 (Men1), in osteoblasts and osteocytes caused osteoporosis despite the preservation of osteoblast differentiation and the bone formation rate. Instead, an increase in osteoclast numbers and bone resorption was detected that persisted even when the deletion of Men1 was restricted to osteocytes. We demonstrate that isolated Men1-deficient osteocytes expressed numerous soluble mediators, such as C-X-C motif chemokine 10 (CXCL10), and that CXCL10-mediated osteoclastogenesis was reduced by CXCL10-neutralizing antibodies. Collectively, our data reveal a novel role for Men1 in osteocyte-osteoclast crosstalk by controlling osteoclastogenesis through the action of soluble factors. A role for Men1 in maintaining bone integrity and thereby preventing osteoporosis is proposed.
Assuntos
Comunicação Celular/fisiologia , Proteínas Proto-Oncogênicas/metabolismo , Fosfatase Alcalina/genética , Fosfatase Alcalina/metabolismo , Animais , Anticorpos Neutralizantes/administração & dosagem , Anticorpos Neutralizantes/imunologia , Células da Medula Óssea/citologia , Diferenciação Celular , Linhagem da Célula , Células Cultivadas , Quimiocina CXCL10/genética , Quimiocina CXCL10/imunologia , Quimiocina CXCL10/metabolismo , Feminino , Fêmur/diagnóstico por imagem , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Osteoclastos/citologia , Osteoclastos/metabolismo , Osteócitos/citologia , Osteócitos/metabolismo , Osteogênese , Osteoporose/etiologia , Osteoporose/metabolismo , Osteoporose/patologia , Proteínas Proto-Oncogênicas/deficiência , Proteínas Proto-Oncogênicas/genética , Fator de Transcrição Sp7/genética , Fator de Transcrição Sp7/metabolismoRESUMO
Hematopoietic stem and progenitor cells reside in vascular and endosteal niches in the bone marrow. Factors affecting bone remodeling were reported to influence numbers and mobilization of hematopoietic stem cells. We therefore analyzed the effects of estradiol acting anabolic on bone integrity. Here we observe that estradiol increases progenitor cell numbers in the vascular but not in the endosteal compartment independent of its estrogen receptor α-dependent anabolic bone effects. Hematopoietic progenitors capable of reconstituting lethally irradiated mice are increased by enhanced cell cycle entry, leading to a diminished long-term reconstitution potential after serial transplantation. We demonstrate that estradiol action on stromal cells potently favors hematopoietic progenitor/stem cell frequency accompanied by enhanced expression of cell adhesion molecules. Finally, estradiol treatment enhances retention of hematopoietic stem cells in the vascular niche of the bone marrow. We describe for the first time the mechanism of estrogen action on hematopoietic stem and progenitor cells.