Mechanosensing and Signaling Crosstalks

  • Toshio Matsumoto
  • Rika Kuriwaka-Kido
  • Shinsuke Kido


Mechanical loading to bone causes mainly two types of stress to bone forming cells, fluid shear stress (FSS) and tensile stress. FSS appears to be a major stress signal that activates osteoblastic/osteocytic intracellular signaling to enhance bone formation. FSS to osteoblasts causes Ca2+ influx by activating a stress-activated cation channel, which activates extracellular signal-regulated kinase (ERK) to the phosphorylate cyclic AMP response element-binding protein (CREB). Phosphorylated CREB binds to the fosB gene promoter to enhance its transcriptional activity, and upregulates the expression of mainly ΔFosB, a C-terminal truncated splice variant of FosB. The increased ΔFosB binds to the 5′AP-1 site on the IL-11 gene promoter and forms a complex with JunD. FSS to osteoblasts also stimulates tyrosine phosphorylation of protein kinase Cδ (PKCδ), which activates Smad1/5. Activated Smad1/5 is bound to the Smad-binding element of the IL-11 gene promoter, and forms a complex with ΔFosB/JunD heterodimer. Thus, Ca2+–ERK–CREB–ΔFosB and PKCδ-Smad1/5 pathways merge together on the IL-11 gene promoter, and the two pathways cooperatively stimulate IL-11 gene expression in response to mechanical stress. The increase in interleukin (IL)-11 then enhances Wnt/β-catenin signaling by suppressing the expression of its inhibitors, dickkopf 1 and 2, in osteoblasts. Thus, the enhanced IL-11 expression by the cooperative AP-1 and Smad1/5 pathways is the upstream signal for stimulation of the main osteogenic pathway, Wnt/β-catenin signaling.


Bone Formation Mechanical Stress Fluid Shear Stress Enhance Bone Formation Sclerostin Expression 



Activator protein-1


Adenosine triphosphate


Bone morphogenetic protein


BMP-specific receptor-regulated Smads


Constitutive nitric oxide synthase


Cyclic AMP response element-binding protein




Extracellular signal-regulated kinase


Fluid shear stress




Inositol triphosphate


Low-density lipoprotein receptor-related protein




Prostaglandin E2


Protein kinase Cδ


Phospholipase C


Receptor activator of nuclear factor-κB ligand


Stress-activated cation channel


Smad-binding element


Transforming growth factor-β


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Copyright information

© Springer 2011

Authors and Affiliations

  • Toshio Matsumoto
    • 1
  • Rika Kuriwaka-Kido
    • 2
  • Shinsuke Kido
    • 3
  1. 1.Department of Medicine and Bioregulatory SciencesThe University of Tokushima and Graduate School of Medical SciencesTokushimaJapan
  2. 2.Department of Medicine and Bioregulatory SciencesThe University of Tokushima and Graduate School of Medical SciencesTokushimaJapan
  3. 3.Department of Medicine and Bioregulatory SciencesThe University of Tokushima and Graduate School of Medical SciencesTokushimaJapan

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