Mechanisms of Mechanotransduction

Orr, A. Wayne; Helmke, Brian P.; Blackman, Brett R.; Schwartz, Martin A.

doi:10.1016/j.devcel.2005.12.006

Cited by 708 publications

(378 citation statements)

References 107 publications

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“…Weight bearing and locomotion stimulate interstitial fluid flow through the bone canalicular system, and the resultant shear stress is thought to be a major mechanism whereby mechanical forces stimulate bone growth (1)(2)(3)(4). Fluid shear stress activates various signal transduction pathways and initiates an anabolic response in osteocytes and osteoblasts, leading to changes in gene expression and increased cell proliferation and differentiation (1,5).…”

mentioning

confidence: 99%

Type II cGMP-dependent Protein Kinase Mediates Osteoblast Mechanotransduction

Rangaswami

Marathe

Zhuang

et al. 2009

Journal of Biological Chemistry

108

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Continuous bone remodeling in response to mechanical loading is critical for skeletal integrity, and interstitial fluid flow is an important stimulus for osteoblast/osteocyte growth and differentiation. However, the biochemical signals mediating osteoblast anabolic responses to mechanical stimulation are incompletely understood. In primary human osteoblasts and murine MC3T3-E1 cells, we found that fluid shear stress induced rapid expression of c-fos, fra-1, fra-2, and fosB/⌬fosB mRNAs; these genes encode transcriptional regulators that maintain skeletal integrity. Fluid shear stress increased osteoblast nitric oxide (NO) synthesis, leading to activation of cGMP-dependent protein kinase (PKG). Pharmacological inhibition of the NO/cGMP/PKG signaling pathway blocked shear-induced expression of all four fos family genes. Induction of these genes required signaling through MEK/Erk, and Erk activation was NO/cGMP/PKG-dependent. Treating cells with a membranepermeable cGMP analog partly mimicked the effects of fluid shear stress on Erk activity and fos family gene expression. In cells transfected with small interfering RNAs (siRNA) specific for membrane-bound PKG II, shear-and cGMP-induced Erk activation and fos family gene expression was nearly abolished and could be restored by transducing cells with a virus encoding an siRNA-resistant form of PKG II; in contrast, siRNA-mediated repression of the more abundant cytosolic PKG I isoform was without effect. Thus, we report a novel function for PKG II in osteoblast mechanotransduction, and we propose a model whereby NO/cGMP/PKG II-mediated Erk activation and induction of c-fos, fra-1, fra-2, and fosB/⌬fosB play a key role in the osteoblast anabolic response to mechanical stimulation.Mechanical stress is a primary determinant of bone growth and remodeling; the strength of bone increases with weight bearing and muscular activity and decreases with unloading and disuse (1, 2). Weight bearing and locomotion stimulate interstitial fluid flow through the bone canalicular system, and the resultant shear stress is thought to be a major mechanism whereby mechanical forces stimulate bone growth (1-4). Fluid shear stress activates various signal transduction pathways and initiates an anabolic response in osteocytes and osteoblasts, leading to changes in gene expression and increased cell proliferation and differentiation (1, 5). As part of this response, a rapid and transient increase in intracellular calcium, nitric oxide (NO), 2 and prostaglandin E 2 occurs, and transcription of genes such as c-fos, cox-2, and igf-1/2 is induced (1, 2, 5).The transcription factor complex AP1, composed of Fos and Jun proteins, plays an essential role in bone development and post-natal skeletal homeostasis (6). De-regulated c-fos expression in mice interferes with normal bone development and induces osteosarcomas, whereas c-Fos-deficient mice develop osteopetrosis because of an early arrest in osteoclast differentiation (7, 8). Mice overexpressing Fra-1, Fra-2, or ⌬FosB (a splice variant of FosB) ex...

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mentioning

confidence: 99%

Type II cGMP-dependent Protein Kinase Mediates Osteoblast Mechanotransduction

Rangaswami

Marathe

Zhuang

et al. 2009

Journal of Biological Chemistry

108

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“…It is well known that hypertension, diabetes and hypercholesterolemia promote atherosclerosis by disrupting the ability of the endothelium to respond to shear stress [1][2][3][4][5][6][7][8][9]. Therefore, elucidation of the mechanisms of shear-mediated signal transduction will greatly advance our understanding of atherosclerosis.…”

Section: Discussionmentioning

confidence: 99%

“…It is well known that ECs transduce the fluid shear stress (FSS) resulting from blood flow into intracellular signals that affect gene expression and cellular functions such as proliferation, apoptosis, migration, permeability, cell alignment and mechanical properties [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]. The activation of signalling pathways by shear forces arises at discrete locations in ECs by force amplification and forceinduced directional biasing of signal propagation [1][2][3][4][10][11][12][16][17][18][20][21][22][23]. Numerous sites have been implicated in transducing mechanical stresses, including the plasma membrane [1,2,5,21,22,24] and its associated glycocalyx [1,5,25 -36], focal adhesions (FAs) [4,7,16,17,37 -43], the nucleus [44,45], the cytoskeleton [4,7,…”

Section: Introductionmentioning

confidence: 99%

Shear-induced force transmission in a multicomponent, multicell model of the endothelium

Dabagh

Jalali

Butler

et al. 2014

J. R. Soc. Interface.

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Haemodynamic forces applied at the apical surface of vascular endothelial cells (ECs) provide the mechanical signals at intracellular organelles and through the inter-connected cellular network. The objective of this study is to quantify the intracellular and intercellular stresses in a confluent vascular EC monolayer. A novel three-dimensional, multiscale and multicomponent model of focally adhered ECs is developed to account for the role of potential mechanosensors (glycocalyx layer, actin cortical layer, nucleus, cytoskeleton, focal adhesions (FAs) and adherens junctions (ADJs)) in mechanotransmission and EC deformation. The overriding issue addressed is the stress amplification in these regions, which may play a role in subcellular localization of mechanotransmission. The model predicts that the stresses are amplified 250-600-fold over apical values at ADJs and 175-200-fold at FAs for ECs exposed to a mean shear stress of 10 dyne cm 22 . Estimates of forces per molecule in the cell attachment points to the external cellular matrix and cell-cell adhesion points are of the order of 8 pN at FAs and as high as 3 pN at ADJs, suggesting that direct force-induced mechanotransmission by single molecules is possible in both. The maximum deformation of an EC in the monolayer is calculated as 400 nm in response to a mean shear stress of 1 Pa applied over the EC surface which is in accord with measurements. The model also predicts that the magnitude of the cell-cell junction inclination angle is independent of the cytoskeleton and glycocalyx. The inclination angle of the cell-cell junction is calculated to be 6.68 in an EC monolayer, which is somewhat below the measured value (9.98) reported previously for ECs subjected to 1.6 Pa shear stress for 30 min. The present model is able, for the first time, to cross the boundaries between different length scales in order to provide a global view of potential locations of mechanotransmission.

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“…Growing evidence suggests that the delivery of non-physiological mechanical stimuli to biological cells can enhance cellular functions such as cell proliferation, stem cell differentiation, gene expression, and signaling pathways [2][3][4][5]. The biochemical signaling response, the so-called mechanotransduction, can be induced through mechanosensitive ion channels, integrin receptor proteins, or tyrosine kinases by mechanical stimuli such as fluid shear stress, hydrostatic pressure, and compressive and stretching mechanical forces [6,7]. The development of microfluidic platforms based on microelectromechanical system (MEMS) technology has opened up new possibilities for revolutionary approaches to enabling the precise spatial and temporal investigation of cellular mechanotransduction processes at the molecular and single-cell level [8,9].…”

Section: Introductionmentioning

confidence: 99%

Fabrication and characterization of cell culture microdevice for nanomechanical stimulation of living cells

Shibata

Umegaki

Ishihara

et al. 2014

AIP Conference Proceedings

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Abstract. In order to elucidate the effects of nanomechanical stimulation on the regulation of cellular functions, we have been developing a cell culture microdevice integrated with piezoelectric thin film actuators. In this paper, we propose a new geometric configuration of the device to allow cell culture on a relatively flat surface and in an open space. An improved fabrication process for PZT actuators overcame a serious problem that sometimes occurred in the previous process; photoresist patterned on PZT film cannot be completely removed due to its degradation in a dry etching process. Then we demonstrate the driving performance of a fabricated prototype microdevice. Moreover, individual cells can be arranged precisely at the desired positions of the PZT actuators by a positive dielectrophoretic force at frequencies above 100 kHz with an application of an AC voltage of 20 V pp . The trapping rate was dramatically improved up to 90% by using microchannel to efficiently supply cells onto the surface of the PZT actuator.

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Mechanisms of Mechanotransduction

Cited by 708 publications

References 107 publications

Type II cGMP-dependent Protein Kinase Mediates Osteoblast Mechanotransduction

Type II cGMP-dependent Protein Kinase Mediates Osteoblast Mechanotransduction

Shear-induced force transmission in a multicomponent, multicell model of the endothelium

Fabrication and characterization of cell culture microdevice for nanomechanical stimulation of living cells

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