title: Beta-catenin levels influence rapid mechanical responses in osteoblasts.
abstract: Mechanical loading of bone initiates an anabolic, anticatabolic pattern of response, yet the molecular events involved in mechanical signal transduction are not well understood. Wnt/beta-catenin signaling has been recognized in promoting bone anabolism, and application of strain has been shown to induce beta-catenin activation. In this work, we have used a preosteoblastic cell line to study the effects of dynamic mechanical strain on beta-catenin signaling. We found that mechanical strain caused a rapid, transient accumulation of active beta-catenin in the cytoplasm and its translocation to the nucleus. This was followed by up-regulation of the Wnt/beta-catenin target genes Wisp1 and Cox2, with peak responses at 4 and 1 h of strain, respectively. The increase of beta-catenin was temporally related to the activation of Akt and subsequent inactivation of GSK3beta, and caveolin-1 was not required for these molecular events. Application of Dkk-1, which disrupts canonical Wnt/LRP5 signaling, did not block strain-induced nuclear translocation of beta-catenin or up-regulation of Wisp1 and Cox2 expression. Conditions that increased basal beta-catenin levels, such as lithium chloride treatment or repression of caveolin-1 expression, were shown to enhance the effects of strain. In summary, mechanical strain activates Akt and inactivates GSK3beta to allow beta-catenin translocation, and Wnt signaling through LRP5 is not required for these strain-mediated responses. Thus, beta-catenin serves as both a modulator and effector of mechanical signals in bone cells.
authors: Department of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599, USA. ncase@med.unc.edu
authors: Natasha
authors: N
authors: Case
authors: Meiyun
authors: M
authors: Ma
authors: Buer
authors: B
authors: Sen
authors: Zhihui
authors: Z
authors: Xie
authors: Ted S
authors: TS
authors: Gross
authors: Janet
authors: J
authors: Rubin
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D001842:Bone and Bones / Q000378:metabolism; D055511:CCN Intercellular Signaling Proteins; D051242:Caveolin 1 / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D051379:Mice; D008954:Models, Biological; D015513:Oncogene Proteins / Q000378:metabolism; D010006:Osteoblasts / Q000378:metabolism*; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins; D015398:Signal Transduction; D051176:beta Catenin / Q000096:biosynthesis* / Q000378:metabolism / Q000502:physiology
chemical_list: D055511:CCN Intercellular Signaling Proteins; C492067:CCN4 protein, mouse; D051242:Caveolin 1; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D051176:beta Catenin; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3