Podosome organization drives osteoclast-mediated bone resorption

Georgess, Dan; Machuca-Gayet, Irma; Blangy, Anne; Jurdic, Pierre

doi:10.4161/cam.27840

Cited by 158 publications

(170 citation statements)

References 123 publications

(181 reference statements)

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“…2(D), left). As a tight seal of the resorbing area is necessary for ef cient bone resorption, 27,32) enhanced development of podosome structures in the CM group is considered to contribute to the excessive activity of osteoclastic resorption.…”

Section: Alterations In the Cellular Organization Of Osteoclasts Diffmentioning

confidence: 99%

Disruption of Collagen Matrix Alignment in Osteolytic Bone Metastasis Induced by Breast Cancer

2016

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Breast cancer is highly metastatic to bone tissue and causes osteolytic lesions through osteoclast activation. Although the effects of osteolytic metastasis on bone quantity have been well studied, whether osteoclast activation induced by cancer bone metastasis affects the bone microstructure, a notable aspect of the bone quality, remains uncertain. The aim of this study was to clarify the effect of osteolytic bone metastasis in breast cancer on the microstructure of the bone matrix, particularly the integrity of collagen bril orientation. Osteolytic breast cancer cells induced hyperactivation of osteoclasts both in vivo and in vitro. Osteoclasts differentiated by culture of monocytes in the cancer cell-derived conditioned medium had an increased number of nuclei; more speci c podosome structures were organized compared to osteoclasts differentiated in the control medium. These observations suggest that the resorptive capacity of a single osteoclast was abnormally upregulated in the cancer-involving environment, causing geometrically irregular resorption cavities. Histological studies on mouse femurs with metastasis of breast cancer MDA-MB-231 cells revealed that the osteoclasts in the metastatic bone were abnormally large and they generated resorption cavities that are irregular both in size and in shape. Notably, collagen matrix in newly formed bone in metastatic bone exhibited a signi cantly disorganized architecture. To the best of our knowledge, this is the rst report demonstrating that osteolytic bone metastasis induces the disruption of bone matrix alignment, which determines the mechanical function of bone in both intact and diseased bone tissue.

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Section: Alterations In the Cellular Organization Of Osteoclasts Diffmentioning

confidence: 99%

Disruption of Collagen Matrix Alignment in Osteolytic Bone Metastasis Induced by Breast Cancer

2016

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“…Odontoclast attachment to the mineral surface is mediated through podosomes, which contain bands of actin filaments and F-actin and actin monomers and which allow further polarization of the clastic cells and integrin-mediated physical interaction with the extracellular matrix (Georgess et al 2014). The integrins are αβ heterodimers, many of whose extracellular domains bind to proteins in the mineral component matrix and their intracellular components to cytoskeleton-organizing and signaling molecules.…”

Section: Clastic Cell Adhesion: Integrins and Extracellular Matrix Prmentioning

confidence: 99%

“…Cell commitment and mononuclear cell fusion are regulated by E-cadherin, which is essential for the cell-to-cell adhesion that mediates fusion of immature osteoclasts precursors (Segeletz and Hoflack 2016). Activated odontoclasts/osteoclasts attach to the mineral matrix, forming a sealing zone and adopting a polarized morphology with ruffled border secretors of proteases that initiate mineral resorption (Georgess et al 2014). A V-ATPase pump carries the protons produced by carbonic anhydrase (CA) II to the ruffled border membrane, releasing them into the resorption pit and generating an acidic microenvironment that is completed by chloride transport (Matsumoto et al 2014).…”

Section: Cellular Components and Adaptations During Root Resorptionmentioning

confidence: 99%

Cellular and Molecular Pathways Leading to External Root Resorption

2016

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External apical root resorption during orthodontic treatment implicates specific molecular pathways that orchestrate nonphysiologic cellular activation. To date, a substantial number of in vitro and in vivo molecular, genomic, and proteomic studies have supplied data that provide new insights into root resorption. Recent mechanisms and developments reviewed here include the role of the cellular component-specifically, the balance of CD68 + , iNOS + M1-and CD68 + , CD163 + M2-like macrophages associated with root resorption and root surface repair processes linked to the expression of the M1-associated proinflammatory cytokine tumor necrosis factor, inducible nitric oxide synthase, the M1 activator interferon γ, the M2 activator interleukin 4, and M2-associated anti-inflammatory interleukin 10 and arginase I. Insights into the role of mesenchymal dental pulp cells in attenuating dentin resorption in homeostasis are also reviewed. Data on recently deciphered molecular pathways are reviewed at the level of (1) clastic cell adhesion in the external apical root resorption process and the specific role of α/β integrins, osteopontin, and related extracellular matrix proteins; (2) clastic cell fusion and activation by the RANKL/RANK/OPG and ATP-P2RX7-IL1 pathways; and (3) regulatory mechanisms of root resorption repair by cementum at the proteomic and transcriptomic levels.

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“…During the differentiation process, osteoclast podosome superstructures evolve from podosome clusters to podosome rings that expand and finally fuse into a belt (Destaing et al, 2003;Georgess et al, 2014;Touaitahuata et al, 2014a). This is accompanied by increasing levels of proteins necessary for podosome belt formation such as Src or Dock5 (Brazier et al, 2006;Vives et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

“…This belt surrounds the ruffled border, a highly convoluted region of the plasma membrane that secretes protons and proteases in contact with the bone. The ruffled border is the actual site where bone resorption takes place (Georgess et al, 2014;Touaitahuata et al, 2014a).…”

Section: Introductionmentioning

confidence: 99%

Tensin 3 is a new partner of Dock5 that controls osteoclast podosome organization and activity

Touaitahuata

Morel

Urbach

et al. 2016

Journal of Cell Science

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Bone resorption by osteoclasts is mediated by a typical adhesion structure called the sealing zone or actin ring, whose architecture is based on a belt of podosomes. The molecular mechanisms driving podosome organization into superstructures remain poorly understood to date, in particular at the osteoclast podosome belt. We performed proteomic analyses in osteoclasts and found that the adaptor protein tensin 3 is a partner of Dock5, a Rac exchange factor necessary for podosome belt formation and bone resorption. Expression of tensin 3 and Dock5 concomitantly increase during osteoclast differentiation. These proteins associate with the osteoclast podosome belt but not with individual podosomes, in contrast to vinculin. Super-resolution microscopy revealed that, even if they colocalize in the x-y plane of the podosome belt, Dock5 and tensin 3 differentially localize relative to vinculin in the z-axis. Tensin 3 increases Dock5 exchange activity towards Rac, and suppression of tensin 3 in osteoclasts destabilizes podosome organization, leading to delocalization of Dock5 and a severe reduction in osteoclast activity. Our results suggest that Dock5 and tensin 3 cooperate for osteoclast activity, to ensure the correct organization of podosomes.

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Podosome organization drives osteoclast-mediated bone resorption

Cited by 158 publications

References 123 publications

Disruption of Collagen Matrix Alignment in Osteolytic Bone Metastasis Induced by Breast Cancer

Disruption of Collagen Matrix Alignment in Osteolytic Bone Metastasis Induced by Breast Cancer

Cellular and Molecular Pathways Leading to External Root Resorption

Tensin 3 is a new partner of Dock5 that controls osteoclast podosome organization and activity

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