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Fluid Shear Stress Induces β-Catenin Signaling in Osteoblasts

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β-Catenin plays a dual role in cells: one at cell–cell junctions and one regulating gene transcription together with TCF (T-cell Factor) in the nucleus. Recently, a role for β-catenin in osteoblast differentiation and gene expression has begun to be elucidated. Herein we investigated the effects of fluid shear stress (FSS) on β-catenin signaling. FSS is a well-characterized anabolic stimulus for osteoblasts; however, the molecular mechanisms for the effects of this stimulation remain largely unknown. We found that 1 hour of laminar FSS (10 dynes/cm2) induced translocation of β-catenin to the nucleus and activated a TCF-reporter gene. Analysis of upstream signals that may regulate β-catenin signaling activity revealed two potential mechanisms for increased β-catenin signaling. First, FSS induced a transient, but significant, increase in the phosphorylation of both glycogen synthase kinase 3β (GSK-3β) and Akt. Second, FSS reduced the levels of β-catenin associated with N-cadherin, suggesting that less sequestration of β-catenin by cadherins occurs in osteoblasts subjected to FSS. Functional analysts of potential genes regulated by β-catenin signaling in osteoblasts revealed two novel observations. First, endogenous, nuclear β-catenin purified from osteoblasts formed a complex with a TCF -binding element in the cyclooxygenase-2 promoter, and, second, overexpression of either a constitutively active β-catenin molecule or inhibition of GSK-3β activity increased basal cyclooxygenase-2 levels. Together, these data demonstrate for the first time that FSS modulates the activity of both GSK-3β and β-catenin and that these signaling molecules regulate cyclooxygenase-2 expression in osteoblasts.

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Acknowledgments

The authors would like to thank S.M. Ponik, R. Gerard, and M. Braun for thoughtful discussions and advice. Thank you also to Dr. Kowalczyk (Emory University) for generously providing mutant β-catenin cDNA. This work was supported by NIH AR 45218, NIH AR 049728, and NASA NAG2 1606 awarded to F.M.P., and NIH AR 45218 awarded to J.P.B.

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  1. Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, 46202, IN, USA

    S. M. Norvell & F. M. Pavalko

  2. Department of Anatomy and Cell Biology, Indiana University School of Medicine, 46202, IN, USA

    M. Alvarez & J. P. Bidwell

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  1. S. M. Norvell
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  2. M. Alvarez
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  3. J. P. Bidwell
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  4. F. M. Pavalko
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Correspondence to S. M. Norvell.

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Norvell, S.M., Alvarez, M., Bidwell, J.P. et al. Fluid Shear Stress Induces β-Catenin Signaling in Osteoblasts. Calcif Tissue Int 75, 396–404 (2004). https://doi.org/10.1007/s00223-004-0213-y

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