Journal Article

Non-Canonical Wnt Signaling and N-Cadherin Related β-Catenin Signaling Play a Role in Mechanically Induced Osteogenic Cell Fate

Tummala, Padmaja, Jacobs, Christopher R., Arnsdorf, Emily J.

2009

Overview

Understanding how the mechanical microenvironment influences cell fate, and more importantly, by what molecular mechanisms, will enhance not only the knowledge of mesenchymal stem cell biology but also the field of regenerative medicine. Mechanical stimuli, specifically loading induced oscillatory fluid flow, plays a vital role in promoting healthy bone development, homeostasis and morphology. Recent studies suggest that such loading induced fluid flow has the potential to regulate osteogenic differentiation via the upregulation of multiple osteogenic genes; however, the molecular mechanisms involved in the transduction of a physical signal into altered cell fate have yet to be determined. Using immuno-staining, western blot analysis and luciferase assays, we demonstrate the oscillatory fluid flow regulates beta-catenin nuclear translocation and gene transcription. Additionally, real time RT-PCR analysis suggests that flow induces Wnt5a and Ror2 upregulation, both of which are essential for activating the small GTPase, RhoA, upon flow exposure. Furthermore, although beta-catenin phosphorylation is not altered by flow, its association with N-cadherin is, indicating that flow-induced beta-catenin signaling is initiated by adherens junction signaling. We propose that the mechanical microenvironment of bone has the potential to regulate osteogenic differentiation by initiating multiple key molecular pathways that are essential for such lineage commitment. Specifically, non-canonical Wnt5a signaling involving Ror2 and RhoA as well as N-cadherin mediated beta-catenin signaling are necessary for mechanically induced osteogenic differentiation.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adherens Junctions - metabolism / Animals / Base Sequence / beta Catenin - metabolism / Biocompatibility / Bioengineering / Biomechanical Phenomena / Bone density / Bones / Cadherins / Cadherins - metabolism / Cell adhesion & migration / Cell Biology/Cell Signaling / Cell Biology/Gene Expression / Cell Differentiation / Cell fate / Cell Line / Developmental Biology/Cell Differentiation / Developmental Biology/Developmental Molecular Mechanisms / Developmental Biology/Stem Cells / Differentiation / Fluid dynamics / Fluid flow / Guanosine triphosphatases / Health promotion / Heparan sulfate / Homeostasis / Kinases / Loading / Mechanical loading / Mechanical stimuli / Mesenchymal stem cells / Mesenchymal Stromal Cells - cytology / Mesenchymal Stromal Cells - metabolism / Mesenchyme / Mice / Models, Biological / Molecular modelling / Morphology / Mutation / N-Cadherin / Nuclear transport / Osteogenesis - physiology / Osteoporosis / Phosphorylation / Polymerase chain reaction / Proteins / Receptor Protein-Tyrosine Kinases - antagonists & inhibitors / Receptor Protein-Tyrosine Kinases - genetics / Receptor Protein-Tyrosine Kinases - metabolism / Receptor Tyrosine Kinase-like Orphan Receptors / Regenerative medicine / rho GTP-Binding Proteins - metabolism / RhoA protein / RNA, Small Interfering - genetics / Signal Transduction / Stem cells / Stress, Mechanical / Transcription / Transcription factors / Translocation / Wnt protein / Wnt Proteins - antagonists & inhibitors / Wnt Proteins - genetics / Wnt Proteins - metabolism / Wnt-5a Protein / Wound healing / β-Catenin