Navegando por Palavras-chave "connexin43"

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    Absence of Cx43 selectively from osteocytes enhances responsiveness to mechanical force in mice
    (Wiley-Blackwell, 2013-07-01) Bivi, Nicoletta; Costa, Rafael Pacheco da [UNIFESP]; Brun, Lucas R.; Murphy, Thomas R.; Farlow, Nathan R.; Robling, Alexander G.; Bellido, Teresita; Plotkin, Lilian I.; Indiana Univ Sch Med; Universidade Federal de São Paulo (UNIFESP); Richard L Roudebush Vet Adm Med Ctr
    The osteocyte network is crucial for the response of bone to mechanical force. Within this network, connexin43 (Cx43) is thought to mediate the communication of osteocytes and osteoblasts among themselves and the exchange of small molecules with the extracellular milieu. Despite recent advances in understanding Cx43 role for the response of bone cells to mechanical stimulation, the contribution of Cx43 specifically in osteocytes to mechanotransduction in vivo is not well-known. We examined the anabolic response to ulnar axial loading of mice lacking Cx43 in osteocytes (Cx43Ot). Loading induced a greater increase in periosteal bone formation rate in Cx43Ot mice compared to control littermates, resulting from higher mineralizing surface and enhanced mineral apposition rate. Expression of -catenin protein, a molecule implicated in mechanotransduction, was higher in bones from Cx43Ot mice, compared to littermate controls. in addition, MLO-Y4 osteocytic cells knocked-down for Cx43 exhibited higher -catenin protein expression and enhanced response to mechanical stimulation. These findings suggest that osteocytes lacking Cx43 are primed to respond to mechanical stimulation and that absence of Cx43 in osteocytes unleashes bone formation, by a mechanism that might involve accumulation of -catenin. (c) 2013 Orthopaedic Research Society Published by Wiley Periodicals, Inc. J Orthop Res 31:10751081, 2013
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    Development of mice with osteoblast-specific connexin43 gene deletion
    (Taylor & Francis Ltd, 2003-07-01) Castro, CHM; Stains, J. P.; Sheikh, S.; Szejnfeld, V. L.; Willecke, K.; Theis, M.; Civitelli, R.; Washington Univ; Universidade Federal de São Paulo (UNIFESP); Univ Bonn; Columbia Univ
    Genetic deficiency of Cx43 in vivo causes skeletal developmental defects, osteoblast dysfunction and perinatal lethality. To determine the role of Cx43 in the adult skeleton, we developed two models of osteoblast-specific Cx43 gene deletion using Cre mediated replacement of a floxed Cx43 allele with a LacZ reporter gene. Cre recombinase expression in osteoblasts was driven by either the osteocalcin OG2 promoter or the 2.3 kb fragment of the Colalpha1(I) promoter. Homozygous Cx43 fl/fl mice, in which the Cx43 coding region is flanked by two loxP sites, were crossed with Cre expressing mice in a heterozygous Cx43-null background [Cx43 +/- ; Colalpha1(I)-Cre or Cx43 +/- ; OG2-Cre]. Cx43 gene ablation was demonstrated in tissues by selective X-gal staining of cells lining the endosteal surface, and in cultured osteoblastic cells from calvaria using different approaches. Although no LacZ expression was observed in proliferating calvaria cells, before osteoblast differentiation begins, post-proliferative cells isolated from conditional knockout mice [Cx43 fl/- ; Colalpha1(I)-Cre or Cx43 fl/- ; OG2-Cre] developed strong LacZ expression as they differentiated, in parallel to a progressive disappearance of Cx43 mRNA and protein abundance relative to controls. Selective Cre mediated Cx43 gene inactivation in bone forming cells will be useful to determine the role of Cx43 in adult skeletal homeostasis and overcome the perinatal lethality of the conventional null model.
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    Low peak bone mass and attenuated anabolic response to parathyroid hormone in mice with an osteoblast-specific deletion of connexin43
    (Company of Biologists Ltd, 2006-10-15) Chung, Dong Jin; Castro, Charlles Heldan de Moura [UNIFESP]; Watkins, Marcus; Stains, Joseph P.; Chung, Min Young; Szejnfeld, Vera Lucia [UNIFESP]; Willecke, Klaus; Theis, Martin; Civitelli, Roberto; Washington Univ; Chonnam Natl Univ; Universidade Federal de São Paulo (UNIFESP); Univ Bonn
    Connexin43 (Cx43) is involved in bone development, but its role in adult bone homeostasis remains unknown. To overcome the postnatal lethality of Cx43 null mutation, we generated mice with selective osteoblast ablation of Cx43, obtained using a Cx43(fl) allele and a 2.3-kb fragment of the alpha(I)(I) collagen promoter to drive Cre in osteoblasts (ColCre). Conditionally osteoblast-deleted ColCre;Cx43(-/fl) mice show no malformations at birth, but develop low peak bone mass and remain osteopenic with age, exhibiting reduced bone formation and defective osteoblast function. By both radiodensitometry and histology, bone mineral content increased rapidly and progressively in adult Cx43(+/fl) mice after subcutaneous injection of parathyroid hormone (PTH), an effect significantly attenuated in ColCre;Cx43(-/fl) mice, with Cx43(-/fl) exhibiting an intermediate response. Attenuation of PTH anabolic action was associated with failure to increase mineral apposition rate in response to PTH in ColCre; Cx43(-/fl), despite an increased osteoblast number, suggesting a functional defect in Cx43-deficient bone-forming cells. in conclusion, lack of Cx43 in osteoblasts leads to suboptimal acquisition of peak bone mass, and hinders the bone anabolic effect of PTH. Cx43 represents a potential target for modulation of bone anabolism.