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•

Balancing forces: architectural control of mechanotransduction

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Christopher C. DuFort¹, Matthew J. Paszek¹, Valerie M. Weaver¹•Institutions (1)

University of California, San Francisco¹

01 May 2011-Nature Reviews Molecular Cell Biology

TL;DR: Sustained disruptions in tensional homeostasis can be caused by alterations in the extracellular matrix, allowing it to serve as a mechanically based memory-storage device that can perpetuate a disease or restore normal tissue behaviour.

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Abstract: All cells exist within the context of a three-dimensional microenvironment in which they are exposed to mechanical and physical cues. These cues can be disrupted through perturbations to mechanotransduction, from the nanoscale-level to the tissue-level, which compromises tensional homeostasis to promote pathologies such as cardiovascular disease and cancer. The mechanisms of such perturbations suggest that a complex interplay exists between the extracellular microenvironment and cellular function. Furthermore, sustained disruptions in tensional homeostasis can be caused by alterations in the extracellular matrix, allowing it to serve as a mechanically based memory-storage device that can perpetuate a disease or restore normal tissue behaviour.

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875 citations

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

...On a more specific level, the spatial presentation of ECM ligands, such as fibronectin, vitronectin, laminin and collagen, and the nanotopography of the ECM, control integrin organization, adhesion assembly, and signal transduction to direct cell behaviou...
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Journal Article•DOI•

Molecular Architecture and Function of Matrix Adhesions

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Benjamin Geiger¹, Kenneth M. Yamada²•Institutions (2)

Weizmann Institute of Science¹, National Institutes of Health²

01 May 2011-Cold Spring Harbor Perspectives in Biology

TL;DR: These cell adhesions play crucial roles in cell migration, proliferation, and determination of cell fate, and are mediated by membrane receptors such as the integrins, as well as many other components that comprise the adhesome.

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Abstract: Cell adhesions mediate important bidirectional interactions between cells and the extracellular matrix. They provide an interactive interface between the extracellular chemical and physical environment and the cellular scaffolding and signaling machinery. This dynamic, reciprocal regulation of intracellular processes and the matrix is mediated by membrane receptors such as the integrins, as well as many other components that comprise the adhesome. Adhesome constituents assemble themselves into different types of cell adhesion structures that vary in molecular complexity and change over time. These cell adhesions play crucial roles in cell migration, proliferation, and determination of cell fate.

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507 citations

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

...Cells can also respond to the micro- or even nano-topography of a surface to which they adhere (Curtis and Wilkinson 1997; Cukierman et al. 2001; Geiger et al. 2001; Baharloo et al. 2005; Grossner-Schreiber et al. 2006; Vogel et al. 2006; Geblinger et al. 2010)....
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...They can assemble into large, belt-like superstructures, and are implicated in matrix-modulating activities (e.g., bone resorption by osteoclasts (Geblinger et al. 2010) and matrix invasion by a variety of cancer cells (Gimona et al. 2008)....
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...2006), regulating their dynamic properties (Geblinger et al. 2010), and modulating their signaling activity....
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...Cells can also respond to the micro-topography or even nano-topography of a surface to which they adhere (Curtis and Wilkinson 1997; Cukierman et al. 2001; Geiger et al. 2001; Baharloo et al. 2005; Grossner-Schreiber et al. 2006; Vogel et al. 2006; Geblinger et al. 2010)....
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...…surface features that are known to play a role in guiding the formation of matrix adhesions (Cukierman et al. 2001; Geiger et al. 2001; Baharloo et al. 2005; Grossner-Schreiber et al. 2006), regulating their dynamic properties (Geblinger et al. 2010) and modulating their signaling activity....
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Journal Article•DOI•

Nanotopographical Control of Stem Cell Differentiation

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Laura E. McNamara¹, Rebecca J. McMurray¹, Manus J.P. Biggs², Fahsai Kantawong¹, Richard O.C. Oreffo³, Matthew J. Dalby¹ - Show less +2 more•Institutions (3)

University of Glasgow¹, Columbia University², University of Southampton³

01 Jan 2010-Journal of Tissue Engineering

TL;DR: Nanotopography is examined as a means to guide differentiation, and its application is described in the context of different subsets of stem cells, with a particular focus on skeletal (mesenchymal) stem cells.

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Abstract: Stem cells have the capacity to differentiate into various lineages, and the ability to reliably direct stem cell fate determination would have tremendous potential for basic research and clinical therapy. Nanotopography provides a useful tool for guiding differentiation, as the features are more durable than surface chemistry and can be modified in size and shape to suit the desired application. In this paper, nanotopography is examined as a means to guide differentiation, and its application is described in the context of different subsets of stem cells, with a particular focus on skeletal (mesenchymal) stem cells. To address the mechanistic basis underlying the topographical effects on stem cells, the likely contributions of indirect (biochemical signal-mediated) and direct (force-mediated) mechanotransduction are discussed. Data from proteomic research is also outlined in relation to topography-mediated fate determination, as this approach provides insight into the global molecular changes at the level of the functional effectors.

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349 citations

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

...diverse cell types including fibroblasts [18, 22], osteoblasts [23], osteoclasts [24, 25], endothelial [15], smooth muscle [26], epithelial [27, 28], and epitenon cells [16]....
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Journal Article•DOI•

Degrading devices: invadosomes in proteolytic cell invasion.

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Stefan Linder, Christiane Wiesner, Mirko Himmel

10 Oct 2011-Annual Review of Cell and Developmental Biology

TL;DR: An overview of the field is provided, with special focus on current developments such as intracellular transport processes, ultrastructural analysis, the possible involvement of invadosomes in disease, and the tentative identification of invadoomes in 3D environments and in vivo.

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Abstract: Podosomes and invadopodia, collectively known as invadosomes, are cell-matrix contacts in a variety of cell types, such as monocytic cells or cancer cells, that have to cross tissue barriers. Both structures share an actin-rich core, which distinguishes them from other matrix contacts, and are regulated by a multitude of signaling pathways including RhoGTPases, kinases, actin-associated proteins, and microtubule-dependent transport. Invadosomes recruit and secrete proteinases and are thus able to lyse extracellular matrix components. They are therefore considered to be potential key structures in proteolytic cell invasion in both physiological and pathological settings. This review provides an overview of the field, with special focus on current developments such as intracellular transport processes, ultrastructural analysis, the possible involvement of invadosomes in disease, and the tentative identification of invadosomes in 3D environments and in vivo.

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346 citations

Journal Article•DOI•

Extracellular matrix networks in bone remodeling.

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Andrea I. Alford¹, Kenneth M. Kozloff¹, Kurt D. Hankenson²•Institutions (2)

University of Michigan¹, Michigan State University²

01 Aug 2015-The International Journal of Biochemistry & Cell Biology

TL;DR: This comprehensive review will focus on how networks of ECM proteins function to regulate osteoclast- and osteoblast-mediated bone remodeling and the clinical significance of these networks on normal bone and as they relate to pathologies of bone mass and geometry will be considered.

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223 citations

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Journal Article•DOI•

Involvement of the Src-cortactin pathway in podosome formation and turnover during polarization of cultured osteoclasts.

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Chen Luxenburg¹, J. Thomas Parsons², Lia Addadi¹, Benjamin Geiger¹•Institutions (2)

Weizmann Institute of Science¹, University of Virginia Health System²

01 Dec 2006-Journal of Cell Science

TL;DR: It is demonstrated that the levels of Podosome-associated actin, and its reorganization in cultured osteoclasts, radically increase upon formation of podosome rings, and is attributable to the downregulation of cortactin activity by its Src-dependent phosphorylation.

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Abstract: Osteoclasts are large, multinucleated cells that adhere to bone via podosomes, and degrade it. During osteoclast polarization, podosomes undergo reorganization from a scattered distribution, through the formation of clusters and ring super-structures, to the assembly of a sealing zone at the cell periphery. In the present study, we demonstrate that the levels of podosome-associated actin, and its reorganization in cultured osteoclasts, radically increase upon formation of podosome rings. At the peripheral ring, actin levels and dynamic reorganization were high, whereas paxillin, associated with the same adhesion super-structure, remained relatively stable. These dynamic changes were regulated by the tyrosine kinase pp60c-Src, whose scaffolding activity supported the assembly of immature stationary podosomes; its catalytic activity was essential for podosome maturation and turnover. The enhanced dynamic reorganization of podosomes during osteoclast polarization was inversely related to the local levels of tyrosine phosphorylation of the Src substrate, cortactin. Furthermore, overexpression of cortactin, mutated at its major Src phosphorylation sites, enhanced actin turnover, suggesting that podosome dynamics in polarizing osteoclasts are attributable to the downregulation of cortactin activity by its Src-dependent phosphorylation.

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103 citations

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

...To address this issue, we immunolabeled the GFP-actin-expressing cells for vinculin (a plaque protein, associated with the adhesive domain of the podosomes and sealing zone), and calculated the difference in net intensity of the two proteins in the sealing zone of osteoclasts cultured on the smooth and rough surfaces....
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...Surfaces were immersed in 70% ethanol for 10 minutes, and conditioned with vitronectin (10 g/ml) for 8-10 hours at 4°C. Prior to cell plating, the calcite slices were washed, placed in the culture medium, and heated to 37°C. Fluorescence microscopy For live cell imaging, RAW cells stably expressing GFP-actin (Luxenburg et al., 2006) were induced to differentiate in plastic dishes for 3 days, then suspended and replated on calcite slices as described above, and observed for 60 hours in sequential periods of 8-12 hours, starting 4 hours after replating, using a DeltaVision microscopy system (Applied Precision, Inc.) consisting of an IX70 inverted microscope equipped with a 20/0....
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...Measurement of actin and vinculin GFP-actin expressing cells were cultured on smooth and rough surfaces for 24 hours prior to permeabilization with 0.5% Triton X-100, and fixation with 3% PFA....
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...Osteoclasts stably expressing GFP-actin were cultured on the smooth and rough regions of the same crystal for 2-4 days, and continuously monitored by time-lapse fluorescence microscopy (1 image/minute) at multiple sites....
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...…were washed, placed in the culture medium, and heated to 37°C. Fluorescence microscopy For live cell imaging, RAW cells stably expressing GFP-actin (Luxenburg et al., 2006) were induced to differentiate in plastic dishes for 3 days, then suspended and replated on calcite slices as described…...
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Journal Article•DOI•

Cytoskeletal changes in osteoclasts during the resorption cycle.

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P T Lakkakorpi¹, H K Väänänen¹•Institutions (1)

University of Oulu¹

01 Feb 1996-Microscopy Research and Technique

TL;DR: Characteristic organization of F-actin into a belt or ring-like structure with a double circle of vinculin around it is needed for the formation of the sealing zone and can thus be used as a marker for resorbing cells.

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Abstract: Osteoclasts are large, multinucleated cells which change their shape and polarity according to their resorptive activity. At least in vitro, nonresorbing osteoclasts move on the bone surface and do not show clear evidence of apical-basolateral polarity. When stimulated for resorption, osteoclasts undergo a rapid reorganization of the cytoskeleton and appear clearly polarized. The detailed nature of different membrane domains in polarized osteoclasts is still far from clear, but a remarkable feature is the formation of a tight sealing zone between the ruffled border and the rest of the cell membrane. Characteristic organization of F-actin into a belt or ring-like structure with a double circle of vinculin around it is needed for the formation of the sealing zone. This type of microfilament organization is typical only for resorbing osteoclasts and can thus be used as a marker for resorbing cells. These characteristic changes in the molecular organization of the cytoskeleton in osteoclasts during the resorption cycle offer several potential targets to inhibit bone resorption, perhaps cell-specific.

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102 citations

Journal Article•DOI•

Intracellular membrane trafficking in bone resorbing osteoclasts.

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Mika T.K. Mulari¹, Jukka Vääräniemi¹, H. Kalervo Väänänen¹•Institutions (1)

University of Turku¹

15 Aug 2003-Microscopy Research and Technique

TL;DR: Details of specific membrane transport processes in the osteoclasts, e.g., the formation of the sealing zone and transcytosis of bone degradation products from the resorption lacuna to the functional secretory domain remain to be clarified.

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Abstract: There is ample evidence now that the two major events in bone resorption, namely dissolution of hydroxyapatite and degradation of the organic matrix, are performed by osteoclasts. The resorption cycle involves several specific cellular activities, where intracellular vesicular trafficking plays a crucial role. Although details of these processes started to open up only recently, it is clear that vesicular trafficking is needed in several specific steps of osteoclast functioning. Several plasma membrane domains are formed during the polarization of the resorbing cells. Multinucleated osteoclasts create a tight sealing to the extracellular matrix as a first indicator of their resorption activity. Initial steps of the sealing zone formation are alpha(v)beta(3)-integrin mediated, but the final molecular interaction(s) between the plasma membrane and mineralized bone matrix is still unknown. A large number of acidic intracellular vesicles then fuse with the bone-facing plasma membrane to form a ruffled border membrane, which is the actual resorbing organelle. The formation of a ruffled border is regulated by a small GTP-binding protein, rab7, which indicates the late endosomal character of the ruffled border membrane. Details of specific membrane transport processes in the osteoclasts, e.g., the formation of the sealing zone and transcytosis of bone degradation products from the resorption lacuna to the functional secretory domain remain to be clarified. It is tempting to speculate that specific features of vesicular trafficking may offer several potential new targets for drug therapy of bone diseases.

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96 citations

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

...The sealing zone structure is composed of a central ring of actin filaments, flanked by inner and outer rings of integrins and several other adhesion proteins (Lakkakorpi and Vaananen, 1996; Mulari et al., 2003)....
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Journal Article•DOI•

PGE2-mediated podosome loss in dendritic cells is dependent on actomyosin contraction downstream of the RhoA-Rho-kinase axis.

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Suzanne F. G. van Helden¹, Machteld M. Oud¹, Ben Joosten¹, Niels Peterse¹, Carl G. Figdor¹, Frank N. van Leeuwen¹ - Show less +2 more•Institutions (1)

Radboud University Nijmegen Medical Centre¹

01 Apr 2008-Journal of Cell Science

TL;DR: The results show that PGE2 stimulation leads to activation of the RhoA–Rho-kinase axis to promote actomyosin-based contraction and subsequent podosome dissolution.

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Abstract: Podosomes are dynamic adhesion structures found in dendritic cells (DCs) and other cells of the myeloid lineage. We previously showed that prostaglandin E2 (PGE2), an important proinflammatory mediator produced during DC maturation, induces podosome disassembly within minutes after stimulation. Here, we demonstrate that this response is mediated by cAMP elevation, occurs downstream of Rho kinase and is dependent on myosin II. Whereas PGE2 stimulation leads to activation of the small GTPase RhoA, decreased levels of Rac1-GTP and Cdc42-GTP are observed. These results show that PGE2 stimulation leads to activation of the RhoA-Rho-kinase axis to promote actomyosin-based contraction and subsequent podosome dissolution. Because podosome disassembly is accompanied by de novo formation of focal adhesions, we propose that the disassembly/formation of these two different adhesion structures is oppositely regulated by actomyosin contractility and relative activities of RhoA, Rac1 and Cdc42.

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84 citations

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

...The assembly of this unique architecture, together with the evidence that actomyosin-based contractility affects podosome turnover (van Helden et al., 2008), suggest that mechanical forces generated by the sealing zone may regulate podosome assembly, and hence, sealing zone turnover....
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Journal Article•DOI•

Cell adhesion and polarisation on molecularly defined spacing gradient surfaces of cyclic RGDfK peptide patches.

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Vera C. Hirschfeld-Warneken¹, Marco Arnold¹, Ada Cavalcanti-Adam¹, Ada Cavalcanti-Adam², Mónica López-García³, Horst Kessler³, Joachim P. Spatz², Joachim P. Spatz¹ - Show less +4 more•Institutions (3)

Max Planck Society¹, Heidelberg University², Technische Universität München³

04 Sep 2008-European Journal of Cell Biology

TL;DR: It is demonstrated how cell morphology, adhesion area, actin and vinculin distribution as well as cell body polarisation are influenced by the peptide patch spacing gradient.

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82 citations

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

...…Redey 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…...
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