Nano-topography sensing by osteoclasts.

doi:10.1242/JCS.060954

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Nano-topography sensing by osteoclasts.

Journal Article•DOI•

Nano-topography sensing by osteoclasts.

Dafna Geblinger¹, Lia Addadi¹, Benjamin Geiger¹•Institutions (1)

Weizmann Institute of Science¹

01 May 2010-Journal of Cell Science (The Company of Biologists Ltd)-Vol. 123, Iss: 10, pp 1503-1510

TL;DR: It was observed that steps or sub-micrometer cracks on the smooth surface stimulate local ring formation, raising the possibility that similar imperfections on bone surfaces may stimulate local osteoclast resorptive activity.

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Abstract: Bone resorption by osteoclasts depends on the assembly of a specialized, actin-rich adhesive ‘sealing zone’ that delimits the area designed for degradation. In this study, we show that the level of roughness of the underlying adhesive surface has a profound effect on the formation and stability of the sealing zone and the associated F-actin. As our primary model substrate, we use ‘smooth’ and ‘rough’ calcite crystals with average topography values of 12 nm and 530 nm, respectively. We show that the smooth surfaces induce the formation of small and unstable actin rings with a typical lifespan of ~8 minutes, whereas the sealing zones formed on the rough calcite surfaces are considerably larger, and remain stable for more than 6 hours. It was further observed that steps or sub-micrometer cracks on the smooth surface stimulate local ring formation, raising the possibility that similar imperfections on bone surfaces may stimulate local osteoclast resorptive activity. The mechanisms whereby the physical properties of the substrate influence osteoclast behavior and their involvement in osteoclast function are discussed.

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Journal Article•DOI•

Bone degradation machinery of osteoclasts: An HIV-1 target that contributes to bone loss.

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Brigitte Raynaud-Messina, Lucie Bracq¹, Maeva Dupont, Shanti Souriant, Shariq M. Usmani², Amsha Proag³, Karine Pingris, Vanessa Soldan², Christophe Thibault, Florence Capilla¹, Talal Al Saati¹, Isabelle Gennero, Pierre Jurdic⁴, Paul Jolicoeur, Jean-Luc Davignon¹, Thorsten R. Mempel², Serge Benichou¹, Isabelle Maridonneau-Parini, Christel Vérollet - Show less +15 more•Institutions (4)

French Institute of Health and Medical Research¹, Harvard University², École Polytechnique³, École Normale Supérieure⁴

13 Mar 2018-Proceedings of the National Academy of Sciences of the United States of America

TL;DR: O osteoclasts constitute HIV-1 host target cells, contributing to bone deficits in vivo and their pathological contribution to bone disorders induced by this virus, in part via Nef, is evidences.

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Abstract: Bone deficits are frequent in HIV-1–infected patients. We report here that osteoclasts, the cells specialized in bone resorption, are infected by HIV-1 in vivo in humanized mice and ex vivo in human joint biopsies. In vitro, infection of human osteoclasts occurs at different stages of osteoclastogenesis via cell-free viruses and, more efficiently, by transfer from infected T cells. HIV-1 infection markedly enhances adhesion and osteolytic activity of human osteoclasts by modifying the structure and function of the sealing zone, the osteoclast-specific bone degradation machinery. Indeed, the sealing zone is broader due to F-actin enrichment of its basal units (i.e., the podosomes). The viral protein Nef is involved in all HIV-1–induced effects partly through the activation of Src, a regulator of podosomes and of their assembly as a sealing zone. Supporting these results, Nef-transgenic mice exhibit an increased osteoclast density and bone defects, and osteoclasts derived from these animals display high osteolytic activity. Altogether, our study evidences osteoclasts as host cells for HIV-1 and their pathological contribution to bone disorders induced by this virus, in part via Nef.

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55 citations

Cites background from "Nano-topography sensing by osteocla..."

...Because the SZ has been related to adhesion and bone degradation capacities of OC (11, 37), we characterized the architecture of this structure in infected OC....
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Journal Article•DOI•

Response of Osteoclasts to Titanium Surfaces with Increasing Surface Roughness: An In Vitro Study

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Jenny Brinkmann¹, Jenny Brinkmann², Thomas Hefti², Falko Schlottig, Nicholas D. Spencer², Heike Hall² - Show less +2 more•Institutions (2)

MESA+ Institute for Nanotechnology¹, ETH Zurich²

25 May 2012-Biointerphases

TL;DR: In general, osteoclasts show similar characteristics on rough titanium surfaces and on bone, but reduced activity on smooth titanium surfaces, which offers some insight into the involvement of osteoclast in remodeling processes around implant surfaces.

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Abstract: Osteoclasts are responsible for bone resorption and implant surface roughness promotes osseointegration. However, little is known about the effect of roughness on osteoclast activity. This study aims at the characterization of osteoclastic response to surface roughness. The number of osteoclasts, the tartrate-resistant acid phosphatase and matrix metalloproteinase (MMP) activities, the cell morphology and the actin-ring formation were examined on smooth (TS), acid-etched (TA) and sandblasted acid-etched (TLA) titanium and on native bone. Cell morphology was comparable on TA, TLA and bone, actin rings being similar in size on TLA and bone, but smaller on TA and virtually absent on TS. Gelatin zymography revealed increased proMMP-9 expression on TA, TLA, and bone compared to TS. In general, osteoclasts show similar characteristics on rough titanium surfaces and on bone, but reduced activity on smooth titanium surfaces. These results offer some insight into the involvement of osteoclasts in remodeling processes around implant surfaces.

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50 citations

Journal Article•DOI•

Bone Is Not Essential for Osteoclast Activation

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Karen Fuller¹, Jade L. Ross¹, Kinga A. Szewczyk¹, Raymond Moss¹, Timothy J. Chambers¹ - Show less +1 more•Institutions (1)

St George's, University of London¹

17 Sep 2010-PLOS ONE

TL;DR: The results show that ligands αvβ3 are not only necessary but sufficient for the induction of resorptive behavior in osteoclasts; and suggest that bone is recognized through its affinity for these ligands, rather than by its mechanical or topographical attributes, or through a putative ‘mineral receptor’.

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Abstract: Background The mechanism whereby bone activates resorptive behavior in osteoclasts, the cells that resorb bone, is unknown. It is known that αvβ3 ligands are important, because blockade of αvβ3 receptor signaling inhibits bone resorption, but this might be through inhibition of adhesion or migration rather than resorption itself. Nor is it known whether αvβ3 ligands are sufficient for resorption the consensus is that bone mineral is essential for the recognition of bone as the substrate appropriate for resorption. Methodology/Principal Findings Vitronectin- but not fibronectin-coated coverslips induced murine osteoclasts to secrete tartrate-resistant acid phosphatase, as they do on bone. Osteoclasts incubated on vitronectin, unlike fibronectin, formed podosome belts on glass coverslips, and these were modulated by resorption-regulating cytokines. Podosome belts formed on vitronectin-coated surfaces whether the substrates were rough or smooth, rigid or flexible. We developed a novel approach whereby the substrate-apposed surface of cells can be visualized in the scanning electron microscope. With this approach, supported by transmission electron microscopy, we found that osteoclasts on vitronectin-coated surfaces show ruffled borders and clear zones characteristic of resorbing osteoclasts. Ruffles were obscured by a film if cells were incubated in the cathepsin inhibitor E64, suggesting that removal of the film represents substrate-degrading behavior. Analogously, osteoclasts formed resorption-like trails on vitronectin-coated substrates. Like bone resorption, these trails were dependent upon resorbogenic cytokines and were inhibited by E64. Bone mineral induced actin rings and surface excavation only if first coated with vitronectin. Fibronectin could not substitute in any of these activities, despite enabling adhesion and cell spreading. Conclusions/Significance Our results show that ligands αvβ3 are not only necessary but sufficient for the induction of resorptive behavior in osteoclasts; and suggest that bone is recognized through its affinity for these ligands, rather than by its mechanical or topographical attributes, or through a putative ‘mineral receptor’.

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50 citations

Cites background from "Nano-topography sensing by osteocla..."

...Another is that rough surfaces stimulate resorption [16]....
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...Another is that it is surface roughness that is recognized [16]....
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...Explanations for the differing size of podosome rings on these two substrates might include differences in surface roughness, which has been shown to influence the size of actin rings [16], or differences in the density of vitronectin bound by the two substrates....
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...It has recently been shown that greater roughness in calcite surfaces stabilizes and enlarges actin structures in osteoclasts [16]....
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Journal Article•DOI•

Osteoclasts on Bone and Dentin In Vitro: Mechanism of Trail Formation and Comparison of Resorption Behavior

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Monika Rumpler, T. Würger, Paul Roschger, Elisabeth Zwettler, I. Sturmlechner, P. Altmann, Peter Fratzl¹, Michael J. Rogers², Klaus Klaushofer - Show less +5 more•Institutions (2)

Max Planck Society¹, Garvan Institute of Medical Research²

11 Sep 2013-Calcified Tissue International

TL;DR: It is shown that trail-forming osteoclasts have crescent-shaped actin rings and provided a model that describes the detailed mechanism, and dentin is a suitable model substrate for data acquisition as long as osteoclast generation is not part of the analyses.

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Abstract: The main function of osteoclasts in vivo is the resorption of bone matrix, leaving behind typical resorption traces consisting of pits and trails. The mechanism of pit formation is well described, but less is known about trail formation. Pit-forming osteoclasts possess round actin rings. In this study we show that trail-forming osteoclasts have crescent-shaped actin rings and provide a model that describes the detailed mechanism. To generate a trail, the actin ring of the resorption organelle attaches with one side outside the existing trail margin. The other side of the ring attaches to the wall inside the trail, thus sealing that narrow part to be resorbed next (3–21 μm). This 3D configuration allows vertical resorption layer-by-layer from the surface to a depth in combination with horizontal cell movement. Thus, trails are not just traces of a horizontal translation of osteoclasts during resorption. Additionally, we compared osteoclastic resorption on bone and dentin since the latter is the most frequently used in vitro model and data are extrapolated to bone. Histomorphometric analyses revealed a material-dependent effect reflected by an 11-fold higher resorption area and a sevenfold higher number of pits per square centimeter on dentin compared to bone. An important material-independent aspect was reflected by comparable mean pit area (μm2) and podosome patterns. Hence, dentin promotes the generation of resorbing osteoclasts, but once resorption has started, it proceeds independently of material properties. Thus, dentin is a suitable model substrate for data acquisition as long as osteoclast generation is not part of the analyses.

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47 citations

Journal Article•DOI•

Substrate adhesion regulates sealing zone architecture and dynamics in cultured osteoclasts.

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Fabian Anderegg¹, Dafna Geblinger², Peter Horvath¹, Mirren Charnley¹, Marcus Textor¹, Lia Addadi², Benjamin Geiger² - Show less +3 more•Institutions (2)

ETH Zurich¹, Weizmann Institute of Science²

05 Dec 2011-PLOS ONE

TL;DR: By growing differentiated osteoclasts on micro-patterned glass substrates, it is shown that SZ growth and fusion strictly depend on the continuity of substrate adhesiveness, at the micrometer scale.

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Abstract: The bone-degrading activity of osteoclasts depends on the formation of a cytoskeletal-adhesive super-structure known as the sealing zone (SZ). The SZ is a dynamic structure, consisting of a condensed array of podosomes, the elementary adhesion-mediating structures of osteoclasts, interconnected by F-actin filaments. The molecular composition and structure of the SZ were extensively investigated, yet despite its major importance for bone formation and remodelling, the mechanisms underlying its assembly and dynamics are still poorly understood. Here we determine the relations between matrix adhesiveness and the formation, stability and expansion of the SZ. By growing differentiated osteoclasts on micro-patterned glass substrates, where adhesive areas are separated by non-adhesive PLL-g-PEG barriers, we show that SZ growth and fusion strictly depend on the continuity of substrate adhesiveness, at the micrometer scale. We present a possible model for the role of mechanical forces in SZ formation and reorganization, inspired by the current data.

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47 citations

Cites background from "Nano-topography sensing by osteocla..."

...In such experimental systems, it was possible to vary individual surface features such as the chemical composition of the surface [7], its dimensionality [9,10], topography [11,12], ligand density [13,14] and rigidity [2,6], and measure the resulting cellular responses....
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...Fusion of neighbouring sealing zones depends on the merger of their adhesion domains SZ fusion, whereby both the actin rings and associated adhesion rings of two SZs merge into one, is a common process in osteoclasts growing on artificial or natural surfaces [11,28,29]....
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...Thus it was shown that osteoclasts respond differentially to the diverse chemical and physical characteristics of bone, including their molecular composition, the degree of mineralization, rigidity and micro-topography [11,29,30,38,39]....
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...[11,29,35,36,37]), the understanding of the mechanisms whereby the cells sense the external surface at a subcellular resolution and accordingly assemble, a resorptive system, is still poor....
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...Notably, the overall size and dynamics of SZs depend very much on the chemical and physical properties of the underlying substrate [11,29]....
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Journal Article•DOI•

Matrix elasticity directs stem cell lineage specification.

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Adam J. Engler¹, Shamik Sen¹, H. Lee Sweeney¹, Dennis E. Discher•Institutions (1)

University of Pennsylvania¹

25 Aug 2006-Cell

TL;DR: Naive mesenchymal stem cells are shown here to specify lineage and commit to phenotypes with extreme sensitivity to tissue-level elasticity, consistent with the elasticity-insensitive commitment of differentiated cell types.

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12,204 citations

"Nano-topography sensing by osteocla..." refers background in this paper

...…cell proliferation, gene expression and cell viability (Bershadsky et al., 2006a; Chen et al., 1997; Diener et al., 2005; Discher et al., 2005; Engler et al., 2006; Geiger et al., 2009; Kunzler et al., 2007; Lo et al., 2000; Roach et al., 2007; Saltel et al., 2004; Vogel and Sheetz, 2006)....
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...…et al., 1999; Roach et al., 2007; Shimizu et al., 1989), local density of the adhesive ligands (Arnold et al., 2004; Arnold et al., 2008; Hirschfeld-Warneken et al., 2008), and physical properties (Bershadsky et al., 2006a; Bershadsky et al., 2006b; Engler et al., 2006; Vogel and Sheetz, 2006)....
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...…a widespread cellular phenomenon, whereby cells collect information on the substrate on which they grow, integrate it, and develop a response (Bershadsky et al., 2006a; Chen et al., 1997; Diener et al., 2005; Discher et al., 2005; Engler et al., 2006; Geiger et al., 2009; Vogel and Sheetz, 2006)....
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...…respond to chemical and physical properties of the underlying matrix, such as rigidity, mechanical activity, ligand density and dimensionality (Bershadsky et al., 2006a; Chen et al., 1997; Diener et al., 2005; Discher et al., 2005; Engler et al., 2006; Geiger et al., 2009; Vogel and Sheetz, 2006)....
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Journal Article•DOI•

Tissue Cells Feel and Respond to the Stiffness of Their Substrate

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Dennis E. Discher¹, Paul A. Janmey¹, Yu-li Wang²•Institutions (2)

University of Pennsylvania¹, University of Massachusetts Medical School²

18 Nov 2005-Science

TL;DR: An understanding of how tissue cells—including fibroblasts, myocytes, neurons, and other cell types—sense matrix stiffness is just emerging with quantitative studies of cells adhering to gels with which elasticity can be tuned to approximate that of tissues.

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Abstract: Normal tissue cells are generally not viable when suspended in a fluid and are therefore said to be anchorage dependent. Such cells must adhere to a solid, but a solid can be as rigid as glass or softer than a baby's skin. The behavior of some cells on soft materials is characteristic of important phenotypes; for example, cell growth on soft agar gels is used to identify cancer cells. However, an understanding of how tissue cells-including fibroblasts, myocytes, neurons, and other cell types-sense matrix stiffness is just emerging with quantitative studies of cells adhering to gels (or to other cells) with which elasticity can be tuned to approximate that of tissues. Key roles in molecular pathways are played by adhesion complexes and the actinmyosin cytoskeleton, whose contractile forces are transmitted through transcellular structures. The feedback of local matrix stiffness on cell state likely has important implications for development, differentiation, disease, and regeneration.

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5,889 citations

"Nano-topography sensing by osteocla..." refers background in this paper

...…a widespread cellular phenomenon, whereby cells collect information on the substrate on which they grow, integrate it, and develop a response (Bershadsky et al., 2006a; Chen et al., 1997; Diener et al., 2005; Discher et al., 2005; Engler et al., 2006; Geiger et al., 2009; Vogel and Sheetz, 2006)....
[...]
...…migration, ECM remodeling, cell proliferation, gene expression and cell viability (Bershadsky et al., 2006a; Chen et al., 1997; Diener et al., 2005; Discher et al., 2005; Engler et al., 2006; Geiger et al., 2009; Kunzler et al., 2007; Lo et al., 2000; Roach et al., 2007; Saltel et al., 2004; Vogel…...
[...]
...…respond to chemical and physical properties of the underlying matrix, such as rigidity, mechanical activity, ligand density and dimensionality (Bershadsky et al., 2006a; Chen et al., 1997; Diener et al., 2005; Discher et al., 2005; Engler et al., 2006; Geiger et al., 2009; Vogel and Sheetz, 2006)....
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Journal Article•DOI•

Geometric control of cell life and death.

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Christopher S. Chen¹, Milan Mrksich¹, Sui Huang¹, George M. Whitesides¹, Donald E. Ingber¹ - Show less +1 more•Institutions (1)

Harvard University¹

30 May 1997-Science

TL;DR: Human and bovine capillary endothelial cells were switched from growth to apoptosis by using micropatterned substrates that contained extracellular matrix-coated adhesive islands of decreasing size to progressively restrict cell extension.

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Abstract: Human and bovine capillary endothelial cells were switched from growth to apoptosis by using micropatterned substrates that contained extracellular matrix-coated adhesive islands of decreasing size to progressively restrict cell extension. Cell spreading also was varied while maintaining the total cell-matrix contact area constant by changing the spacing between multiple focal adhesion-sized islands. Cell shape was found to govern whether individual cells grow or die, regardless of the type of matrix protein or antibody to integrin used to mediate adhesion. Local geometric control of cell growth and viability may therefore represent a fundamental mechanism for developmental regulation within the tissue microenvironment.

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4,641 citations

"Nano-topography sensing by osteocla..." refers background in this paper

...…a widespread cellular phenomenon, whereby cells collect information on the substrate on which they grow, integrate it, and develop a response (Bershadsky et al., 2006a; Chen et al., 1997; Diener et al., 2005; Discher et al., 2005; Engler et al., 2006; Geiger et al., 2009; Vogel and Sheetz, 2006)....
[...]
...…respond to chemical and physical properties of the underlying matrix, such as rigidity, mechanical activity, ligand density and dimensionality (Bershadsky et al., 2006a; Chen et al., 1997; Diener et al., 2005; Discher et al., 2005; Engler et al., 2006; Geiger et al., 2009; Vogel and Sheetz, 2006)....
[...]
...…cellular processes, including adhesion, migration, ECM remodeling, cell proliferation, gene expression and cell viability (Bershadsky et al., 2006a; Chen et al., 1997; Diener et al., 2005; Discher et al., 2005; Engler et al., 2006; Geiger et al., 2009; Kunzler et al., 2007; Lo et al., 2000; Roach…...
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Journal Article•DOI•

Cell Movement Is Guided by the Rigidity of the Substrate

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Chun Min Lo¹, Hong Bei Wang¹, Micah Dembo², Yu-li Wang¹•Institutions (2)

University of Massachusetts Medical School¹, Boston University²

01 Jul 2000-Biophysical Journal

TL;DR: It is discovered that changes in tissue rigidity and strain could play an important controlling role in a number of normal and pathological processes involving cell locomotion, including morphogenesis, the immune response, and wound healing.

...read moreread less

3,189 citations

"Nano-topography sensing by osteocla..." refers background in this paper

...…cell proliferation, gene expression and cell viability (Bershadsky et al., 2006a; Chen et al., 1997; Diener et al., 2005; Discher et al., 2005; Engler et al., 2006; Geiger et al., 2009; Kunzler et al., 2007; Lo et al., 2000; Roach et al., 2007; Saltel et al., 2004; Vogel and Sheetz, 2006)....
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Journal Article•DOI•

Taking Cell-Matrix Adhesions to the Third Dimension

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Edna Cukierman¹, Roumen Pankov¹, Daron R. Stevens¹, Kenneth M. Yamada¹•Institutions (1)

National Institutes of Health¹

23 Nov 2001-Science

TL;DR: These distinctive in vivo 3D-matrix adhesions differ in structure, localization, and function from classically described in vitro adhesion, and as such they may be more biologically relevant to living organisms.

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Abstract: Adhesions between fibroblastic cells and extracellular matrix have been studied extensively in vitro, but little is known about their in vivo counterparts. Here, we characterized the composition and function of adhesions in three-dimensional (3D) matrices derived from tissues or cell culture. "3D-matrix adhesions" differ from focal and fibrillar adhesions characterized on 2D substrates in their content of alpha5beta1 and alphavbeta3 integrins, paxillin, other cytoskeletal components, and tyrosine phosphorylation of focal adhesion kinase (FAK). Relative to 2D substrates, 3D-matrix interactions also display enhanced cell biological activities and narrowed integrin usage. These distinctive in vivo 3D-matrix adhesions differ in structure, localization, and function from classically described in vitro adhesions, and as such they may be more biologically relevant to living organisms.

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3,000 citations

"Nano-topography sensing by osteocla..." refers background in this paper

...Many cell types react to changes in the threedimensional texture of the substrate at the nanometer- and micrometer scales, by altering their adhesion, motility and orientation (Cukierman et al., 2001; Curtis and Wilkinson, 1997; Geiger, 2001; Vogel and Sheetz, 2006)....
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...The interplay between topography, force and adhesion dynamics might also affect other, mechanosensitive adhesions such as focal adhesions, possibly accounting for changes in their stability, signaling activity and dynamics, when plated on a rough threedimensional matrix (Cukierman et al., 2001)....
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