The Mode of Mechanical Integrin Stressing Controls Intracellular Signaling in Osteoblasts

Pommerenke, Hagen; Schmidt, Christian; Dürr, Frieda; Nebe, Barbara; Lüthen, Frank; Müller, Petra; Rychly, Joachim

doi:10.1359/jbmr.2002.17.4.603

Cited by 85 publications

(72 citation statements)

References 40 publications

(42 reference statements)

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“…However, the evolution of the FAK phosphorylation state in adherent cells that are submitted to mechanical strain remains poorly investigated. Pommerenke et al showed that twisting magnetic beads coated with anti-␤1 antibodies and bound to osteoblastic cells leads to FAK activation (14). In the present study, immunostaining of phosphotyrosine residues essentially localized to focal adhesion plaques.…”

Section: Discussionsupporting

confidence: 67%

“…Recent reports demonstrated that mechanical strain is able to activate ERK1/2 in several adherent cells such as mesangial cells (6), smooth muscle cells (7), and chondrocytes (8). In osteoblasts, ERK activation was mostly reported in fluid flow (9 -12), centrifugation (13), or magnetic drag force (14) experiments and in only one study using cyclic stretch (albeit combined with fluid flow) (15). However, cell stretch appears to be a relevant model of mechanical stimulus in the bone field (16,17) and provides specific osteoblastic responses (18).…”

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confidence: 99%

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Mechanical Strain on Osteoblasts Activates Autophosphorylation of Focal Adhesion Kinase and Proline-rich Tyrosine Kinase 2 Tyrosine Sites Involved in ERK Activation

Boutahar

Guignandon

Vico

et al. 2004

Journal of Biological Chemistry

170

140

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The mechanisms involved in the mechanical loadinginduced increase in bone formation remain unclear. In this study, we showed that cyclic strain (CS) (10 min, 1% stretch at 0.25 Hz) stimulated the proliferation of overnight serum-starved ROS 17/2.8 osteoblast-like cells plated on type I collagen-coated silicone membranes. This increase was blocked by MEK inhibitor PD-98059. Signaling events were then assessed 0 min, 30 min, and 4 h after one CS period with Western blotting and coimmunoprecipitation. CS rapidly and time-dependently promoted phosphorylation of both ERK2 at Tyr-187 and focal adhesion kinase (FAK) at Tyr-397 and Tyr-925, leading to the activation of the Ras/Raf/MEK pathway. Cell transfection with FAK mutated at Tyr-397 completely blocked ERK2 Tyr-187 phosphorylation. Quantitative immunofluorescence analysis of phosphotyrosine residues showed an increase in focal adhesion plaque number and size in strained cells. CS also induced both Src-Tyr-418 phosphorylation and Src to FAK association. Treatment with the selective Src family kinase inhibitor pyrazolopyrimidine 2 did not prevent CS-induced FAK-Tyr-397 phosphorylation suggesting a Srcindependent activation of FAK. CS also activated proline-rich tyrosine kinase 2 (PYK2), a tyrosine kinase highly homologous to FAK, at the 402 phosphorylation site and promoted its association to FAK in a time-dependent manner. Mutation of PYK2 at the Tyr-402 site prevented the ERK2 phosphorylation only at 4 h. Intra and extracellular calcium chelators prevented PYK2 activation only at 4 h. In summary, our data showed that osteoblast response to mitogenic CS was mediated by MEK pathway activation. The latter was induced by ERK2 phosphorylation under the control of FAK and PYK2 phosphorylation orchestrated in a time-dependent manner.

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Section: Discussionsupporting

confidence: 67%

mentioning

confidence: 99%

Mechanical Strain on Osteoblasts Activates Autophosphorylation of Focal Adhesion Kinase and Proline-rich Tyrosine Kinase 2 Tyrosine Sites Involved in ERK Activation

Boutahar

Guignandon

Vico

et al. 2004

Journal of Biological Chemistry

170

140

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“…Osteoblasts as well as tumour cells express various integrins, and integrin signals are known to regulate osteoclast formation (Matsuura et al, 1996;Akatsu et al, 1998;Pommerenke et al, 2002). The molecules involved in cell-tocell recognition between MDA-231 cells and osteoblasts and the signal transduction for RANKL expression in osteoblasts are under investigation in our laboratory.…”

Section: Discussionmentioning

confidence: 99%

Role of RANKL-induced osteoclast formation and MMP-dependent matrix degradation in bone destruction by breast cancer metastasis

et al. 2003

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Bone metastasis of breast cancer induces severe osteolysis with increased bone resorption. Osteoclast differentiation regulated by the receptor activator of NF-kB ligand (RANKL) in osteoblasts and matrix degradation induced by matrix metalloproteinases (MMPs) are thought to be involved in the process of bone resorption. When nude mice were inoculated with human breast cancer cells, MDA-MB-231(MDA-231), numerous osteoclasts resorbed bone and the degradation of the bone matrix markedly progressed in the femur and tibia with metastasis of the MDA-231 tumour. The expression of RANKL, MMP-13 and membrane-type 1-MMP mRNA was markedly elevated in bone with metastasis. When MDA-231 cells were cocultured with mouse calvaria, MDA-231 markedly induced bone resorption measured by calcium release from the calvaria, and the expression of RANKL, MMP-2 and MMP-13 was elevated in the calvaria after the coculture. The separation of MDA-231 from the calvaria using filter insert showed decreased bone resorption, suggesting that cell-to-cell interaction is essential for cancer-induced bone resorption. Adding MDA-231 cells to bone marrow cultures markedly induced osteoclast formation, and the expression of RANKL in osteoblasts was enhanced by contact with the cell surface of MDA-231 cells. These results indicate that RANKL-induced osteoclast formation and MMP-dependent matrix degradation are associated with osteolysis because of bone metastasis of breast cancer.

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“…The mechanical interaction of integrins with the cytoskeleton involves accumulation of a number of cytoskeletally associated proteins [39,40]. Studies to directly apply mechanical forces to integrins on the apical surface of cells, provided insights into signaling mechanisms and biological responses of osteoblasts and mesenchymal stem cells [41][42][43][44]. These studies demonstrated a role of intracellular calcium in intracellular signaling which is required to activate and immobilize signaling proteins, like focal adhesion kinase to the actin cytoskeleton.…”

Section: Cells and Mechanotransductionmentioning

confidence: 99%

Cell-material interaction

Rychly

Nebe

2013

BioNanoMaterials

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Abstract:The interaction of cells with material surfaces is of fundamental relevance and contributes to the clinical success of implants. Cells sense their physico-chemical environment resulting in focal adhesion reorganization, spatio-temporal localization and activation of integrin dependent signalling proteins as well as phenotypic changes, e.g., of the actin cytoskeleton. The technology of designing instructive biomaterials involves chemical modifications by grafting of chemical groups, adhesion ligands and growth factors. Physical modifications of the materials are created by structuring the surfaces stochastically and geometrically and by modifications of the material stiffness. Insights into the mechanism at the interface that are involved in the regulation of cells such as stem cells, osteoblasts and chondrocytes by materials will advance the development of innovative biomaterials in regenerative medicine.

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The Mode of Mechanical Integrin Stressing Controls Intracellular Signaling in Osteoblasts

Abstract: ABSTRACT

Cited by 85 publications

References 40 publications

Mechanical Strain on Osteoblasts Activates Autophosphorylation of Focal Adhesion Kinase and Proline-rich Tyrosine Kinase 2 Tyrosine Sites Involved in ERK Activation

Mechanical Strain on Osteoblasts Activates Autophosphorylation of Focal Adhesion Kinase and Proline-rich Tyrosine Kinase 2 Tyrosine Sites Involved in ERK Activation

Role of RANKL-induced osteoclast formation and MMP-dependent matrix degradation in bone destruction by breast cancer metastasis

Cell-material interaction

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