Rac1 GTPase silencing counteracts microgravity‐induced effects on osteoblastic cells

Guignandon, Alain; Faure, Céline; Neutelings, Thibault; Rattner, Aline; Mineur, Pierre; Linossier, Marie‐Thérèse; Laroche, Norbert; Lambert, Charles; Deroanne, Christophe; Nusgens, Betty; Demets, R.; Colige, Alain; Vico, Laurence

doi:10.1096/fj.14-249714

Cited by 29 publications

(18 citation statements)

References 52 publications

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“…It may either directly stimulate actin polymerization, or it may interact with PAK1 that in turn is implicated in actin reorganization . The data presented here provide strong evidence that Rac1 (and PAK1) are mainly involved in both, actin redistribution and Fgf23 gene transcription, supporting previous studies, which established an important role of Rac1 in osteoblastic cells . Although at present, we cannot exclude that also other small Rho‐GTPases, such as RhoA/B‐ signaling, may as well be involved, our findings strongly indicate that Rac1/PAK1‐stimulated actin redistribution is required for the 1,25(OH) 2 D 3 ‐induced production of FGF23 in UMR106 osteoblast‐like cells.…”

Section: Discussionsupporting

confidence: 87%

Fibroblast growth factor (Fgf) 23 gene transcription depends on actin cytoskeleton reorganization

et al. 2016

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Edited by Lukas Alfons HuberThe consequence is a decrease in the plasma concentration of phosphate and 1,25(OH) 2 D 3 , the biologically active form of vitamin D. To mediate these renal effects, FGF23 requires aKlotho as a co-receptor [4,5].In addition, FGF23 is a powerful counteracter of aging. Mice deficient for FGF23 or for aKlotho suffer from rapid aging with a life span of a few weeks only and numerous age-related diseases [5,6]. The rapid aging is directly or indirectly dependent on the hyperphosphatemia of the mice as feeding them a low-phosphate or low-vitamin D diet greatly expands their life span [7].In contrast, excess FGF23 production due to FGF23-synthesizing tumors in men results in osteomalacia [8]. The regulation of FGF23 formation by bone cells has remained ill-defined. Among the known triggers of FGF23 expression are parathyroid hormone (PTH) [9][10][11], 1,25(OH) 2 D 3 [12,13] and increased dietary phosphorus intake [14,15]. Mutations of the dentin Abbreviations 1,25(OH) 2 D 3, calcitriol; Fgf, fibroblast growth factor; NFjB, nuclear factor kappa B; PI3, phosphoinositide-3; PTH, parathyroid hormone; PVDF, polyvinylidene fluoride; TNF, tumor necrosis factor; VDR, vitamin D receptor. 705FEBS Letters 590 (2016) 705-715 ª

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Section: Discussionsupporting

confidence: 87%

Fibroblast growth factor (Fgf) 23 gene transcription depends on actin cytoskeleton reorganization

et al. 2016

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“…The cytoskeleton is discussed as the initial gravity sensor [26]. For example, bone cells exposed to r- and s-µ g show changes in their cytoskeleton and focal adhesions, two major mechanosensitive structures [27,28]. Similar results were obtained when investigating thyroid cancer and melanoma cells cultured under µ g -conditions [14,29].…”

Section: Discussionmentioning

confidence: 84%

Real Microgravity Influences the Cytoskeleton and Focal Adhesions in Human Breast Cancer Cells

Nassef

Kopp

Wehland

et al. 2019

IJMS

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With the increasing number of spaceflights, it is crucial to understand the changes occurring in human cells exposed to real microgravity (r-µg) conditions. We tested the effect of r-µg on MCF-7 breast cancer cells with the objective to investigate cytoskeletal alterations and early changes in the gene expression of factors belonging to the cytoskeleton, extracellular matrix, focal adhesion, and cytokines. In the Technische Experimente unter Schwerelosigkeit (TEXUS) 54 rocket mission, we had the opportunity to conduct our experiment during 6 min of r-µg and focused on cytoskeletal alterations of MCF-7 breast cancer cells expressing the Lifeact-GFP marker protein for the visualization of F-actin as well as the mCherry-tubulin fusion protein using the Fluorescence Microscopy Analysis System (FLUMIAS) for fast live-cell imaging under r-µg. Moreover, in a second mission we investigated changes in RNA transcription and morphology in breast cancer cells exposed to parabolic flight (PF) maneuvers (31st Deutsches Zentrum für Luft- und Raumfahrt (DLR) PF campaign). The MCF-7 cells showed a rearrangement of the F-actin and tubulin with holes, accumulations in the tubulin network, and the appearance of filopodia- and lamellipodia-like structures in the F-actin cytoskeleton shortly after the beginning of the r-µg period. PF maneuvers induced an early up-regulation of KRT8, RDX, TIMP1, CXCL8 mRNAs, and a down-regulation of VCL after the first parabola. E-cadherin protein was significantly reduced and is involved in cell adhesion processes, and plays a significant role in tumorigenesis. Changes in the E-cadherin protein synthesis can lead to tumor progression. Pathway analyses indicate that VCL protein has an activating effect on CDH1. In conclusion, live-cell imaging visualized similar changes as those occurring in thyroid cancer cells in r-µg. This result indicates the presence of a common mechanism of gravity perception and sensation.

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“…Many previous reports clearly demonstrated cytoskeletal alterations after much shorter time in microgravity. Cytoskeletal changes in a microgravity environment have been reported in the time frame of seconds in ML-1 human follicular thyroid cancer cells [ 30 ] and in EA.hy926 human endothelial cells [ 31 ], in the frame of minutes in A431 human epidermoid cancer cells [ 32 ], Jurkat T cells [ 33 ], FTC-133 cells [ 34 ] and in the frame of hours until days in J-111 cells [ 16 , 17 ], MC3T3 osteoblasts [ 35 ], Jurkat T cells [ 36 ], MCF-7 human breast cancer cells [ 37 ], primary rat cardiomyocytes [ 38 ] and human MG-63 osteoblast-like cells [ 39 ]. These studies observed different cytoskeletal alterations such as clustering and more perinuclear localization of microtubules, perinuclear localization and clustering of intermediate filaments with larger meshes and perinuclear and cortical redistribution of actin fibers, which were reduced in number, length and thickness [ 40 ].…”

Section: Discussionmentioning

confidence: 99%

Cytoskeletal stability and metabolic alterations in primary human macrophages in long-term microgravity

et al. 2017

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The immune system is one of the most affected systems of the human body during space flight. The cells of the immune system are exceptionally sensitive to microgravity. Thus, serious concerns arise, whether space flight associated weakening of the immune system ultimately precludes the expansion of human presence beyond the Earth's orbit. For human space flight, it is an urgent need to understand the cellular and molecular mechanisms by which altered gravity influences and changes the functions of immune cells. The CELLBOX-PRIME (= CellBox-Primary Human Macrophages in Microgravity Environment) experiment investigated for the first time microgravity-associated long-term alterations in primary human macrophages, one of the most important effector cells of the immune system. The experiment was conducted in the U.S. National Laboratory on board of the International Space Station ISS using the NanoRacks laboratory and Biorack type I standard CELLBOX EUE type IV containers. Upload and download were performed with the SpaceX CRS-3 and the Dragon spaceship on April 18th, 2014 / May 18th, 2014. Surprisingly, primary human macrophages exhibited neither quantitative nor structural changes of the actin and vimentin cytoskeleton after 11 days in microgravity when compared to 1g controls. Neither CD18 or CD14 surface expression were altered in microgravity, however ICAM-1 expression was reduced. The analysis of 74 metabolites in the cell culture supernatant by GC–TOF–MS, revealed eight metabolites with significantly different quantities when compared to 1g controls. In particular, the significant increase of free fucose in the cell culture supernatant was associated with a significant decrease of cell surface–bound fucose. The reduced ICAM-1 expression and the loss of cell surface–bound fucose may contribute to functional impairments, e.g. the activation of T cells, migration and activation of the innate immune response. We assume that the surprisingly small and non-significant cytoskeletal alterations represent a stable “steady state” after adaptive processes are initiated in the new microgravity environment. Due to the utmost importance of the human macrophage system for the elimination of pathogens and the clearance of apoptotic cells, its apparent robustness to a low gravity environment is crucial for human health and performance during long-term space missions.

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Rac1 GTPase silencing counteracts microgravity‐induced effects on osteoblastic cells

Cited by 29 publications

References 52 publications

Fibroblast growth factor (Fgf) 23 gene transcription depends on actin cytoskeleton reorganization

Fibroblast growth factor (Fgf) 23 gene transcription depends on actin cytoskeleton reorganization

Real Microgravity Influences the Cytoskeleton and Focal Adhesions in Human Breast Cancer Cells

Cytoskeletal stability and metabolic alterations in primary human macrophages in long-term microgravity

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