Cytoskeleton dynamics and osteoclast biology

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Visualization of osteoclasts by microscopy. Left: Osteoclast in fluorescence microscopy with podosomes in blue and microtubules in red; center: osteoclast on bone in scanning electron microscopy; right: detail of an osteoclast in high resolution fluorescence microscopy with podosomes in blue and microtubules in green.

Osteoclasts: cells that maintain our bones but can also destroy them.

The bone is a very dynamic tissue, destroying itself and rebuilding itself permanently. This dynamism is ensured by a good coordination between the cells that destroy the old bone, osteoclasts, and those that rebuild it, the osteoblasts. In some diseases, the destruction of bone by osteoclasts takes over bone formation. The uncontrolled activity of osteoclasts leads to osteoporosis, which strongly affects the quality of life and independence of many people. We seek to understand how the osteoclast organizes its bone resorption apparatus, a kind of sucker that allows them to stick to the bone. To destroy bone, osteoclasts use particular cell structures: the podosomes. These act as snaps between the bone and the osteoclast, and they are organized into circles inside which the bone is degraded.

Cytoskeleton dynamics is at the basis of bone resorption regulation.

The bone resorption apparatus of osteoclast consists of podosomes, formed of actin and regulatory proteins; they are organized into a belt maintained by microtubules. We study the regulation of actin and tubulin cytoskeleton dynamics in osteoclasts, in order to understand the mechanisms that control their bone resorption activity.

By identifying the key regulators of the bone resorption apparatus, we hope to eventually pave the way for new osteoporosis treatments that are as or even more effective, but with fewer adverse effects, than the currently available drugs.

SBCF affiliated team                                    Team membre of the Invadosome consortium 

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Anne Blangy

+33 (0)4 34 35 95 08

Members of the team

  • Anne BLANGY Group Leader
    (Staff Scientist) +33 (0)4 34 35 95 08
  • Guillaume BOMPARD
    (Staff Scientist) +33 (0)4 34 35 95 07
  • Justine MAURIN
    (PhD Student) +33 (0)4 34 35 95 07
  • Anne MOREL
    (Research Assistant) +33 (0)4 34 35 95 08
  • Virginie VIVES
    (Staff Scientist) +33 (0)4 34 35 95 07
    • 2020

      The atypical Rho GTPase RhoU interacts with intersectin-2 to regulate endosomal recycling pathways

      Gubar O, Croisé P, Kropyvko S, Gryaznova T, Tóth P, Blangy A, Vitale N, Rynditch A, Gasman S, Ory S.

      J Cell Sci. 2020 Aug 27;133(16):jcs234104. doi: 10.1242/jcs.234104. Pubmed

    • 2020

      Novel 2,7-Diazaspiro[4,4]nonane Derivatives to Inhibit Mouse and Human Osteoclast Activities and Prevent Bone Loss in Ovariectomized Mice without Affecting Bone Formation

      Mounier L, Morel A, Ferrandez Y, Morko J, Vääräniemi J, Gilardone M, Roche D, Cherfils J, Blangy A.

      J Med Chem. 2020 Nov 25;63(22):13680-13694. doi: 10.1021/acs.jmedchem.0c01201 Pubmed

    • 2020

      Regulation of invadosomes by microtubules: Not only a matter of railways.

      Maurin J, Blangy A, Bompard G.

      Eur J Cell Biol. 2020 Aug 21;99(7):151109. doi: 10.1016/j.ejcb.2020.151109 Pubmed

    • 2020

      The osteoclast cytoskeleton – current understanding and therapeutic perspectives for osteoporosis

      Anne Blangy, Guillaume Bompard, David Guerit, Pauline Marie, Justine Maurin, Anne Morel, Virginie Vives

      Journal of Cell Science 2020 133: jcs244798 doi: 10.1242/jcs.244798 Published 1 July 2020 Pubmed

    • 2020

      Primary Myeloid Cell Proteomics and Transcriptomics: Importance of β-tubulin Isotypes for Osteoclast Function

      Guérit D, Marie P, Morel A, Maurin J, Verollet C, Raynaud-Messina B, Urbach S, Blangy A.

      J Cell Sci. 2020 May 27;133(10):jcs239772. doi: 10.1242/jcs.239772. Pubmed

    • 2019

      Dock5 is a new regulator of microtubule dynamic instability in osteoclasts.

      Guimbal S, Morel A, Guérit D, Chardon M, Blangy A, Vives V.

      Biol Cell. 2019 Aug 28. doi: 10.1111/boc.201900014 Pubmed

    • 2019

      IFT88 controls NuMA enrichment at k-fibers minus-ends to facilitate their re-anchoring into mitotic spindles.

      Taulet N, Douanier A, Vitre B, Anguille C, Maurin J, Dromard Y, Georget V, Delaval B.

      Sci Rep. 9(1):10311. Pubmed

    • 2019

      The atypical RhoU/Wrch1 Rho GTPase controls cell proliferation and apoptosis in the gut epithelium.

      Slaymi C, Vignal E, Crès G, Roux P, Blangy A, Raynaud P, Fort P.

      Biol Cell. 2019 May;111(5):121-141 Pubmed

    • 2018

      Methods to Investigate the Role of Rho GTPases in Osteoclast Function.

      Morel A, Blangy A, Vives V.

      Methods Mol Biol. 2018;1821:219-233. Pubmed

    • 2018

      Combined strategy of siRNA and osteoclast actin cytoskeleton automated imaging to identify novel regulators of bone resorption shows a non-mitotic function for anillin.

      Maurin J, Morel A, Hassen-Khodja C, Vives V, Jurdic P, Machuca-Gayet I, Blangy A.

      Eur J Cell Biol. 2018 Nov;97(8):568-579. Pubmed

    • 2018

      CSAP Acts as a Regulator of TTLL-Mediated Microtubule Glutamylation

      Bompard G, van Dijk J, Cau J, Lannay Y, Marcellin G, Lawera A, van der Laan S, Rogowski K.

      Cell Rep. 25(10):2866-2877 Pubmed

    • 2017

      Allosteric inhibition of the guanine nucleotide exchange factor DOCK5 by a small molecule.

      Ferrandez Y, Zhang W, Peurois F, Akendengué L, Blangy A, Zeghouf M, Cherfils J.

      Sci Rep. 7(1):14409. Pubmed

    • 2017

      The Evolutionary Landscape of Dbl-Like RhoGEF Families: Adapting Eukaryotic Cells to Environmental Signals

      Fort P, Blangy A.

      Genome Biol Evol. 9:1471-1486. Pubmed

    • 2017

      Tensins are versatile regulators of Rho GTPase signalling and cell adhesion

      A. Blangy

      Biol Cell. 109:115-126. Pubmed

    • 2016

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

      Touaitahuata H, Morel A, Urbach S, Mateos-Langerak J, de Rossi S, Blangy A.

      J Cell Sci., 129:3449-61. Pubmed

    • 2016

      The RhoE/ROCK/ARHGAP25 signaling pathway controls cell invasion by inhibition of Rac activity.

      Thuault S, Comunale F, Hasna J, Fortier M, Planchon D, Elarouci N, De Reynies A, Bodin S, Blangy A, Gauthier-Rouvière[...]

      Mol Biol Cell. 27:2653-61. Pubmed

    • 2016

      TOM1L1 drives membrane delivery of MT1-MMP to promote ERBB2-induced breast cancer cell invasion.

      Chevalier C, Collin G, Descamps S, Touaitahuata H, Simon V, Reymond N, Fernandez L, Milhiet PE, Georget V, Urbach S,[...]

      Nat Commun. 7:10765. Pubmed

    • 2015

      Pharmacological inhibition of Dock5 prevents osteolysis by affecting osteoclast podosome organization while preserving bone formation.

      Vives V, Cres G, Richard C, Busson M, Ferrandez Y, Planson AG, Zeghouf M, Cherfils J, Malaval L, Blangy A.

      Nat Commun. 6:6218. Pubmed

    • 2015

      A novel therapeutic approach to fight osteoporosis: disrupt osteoclast activity without affecting bone formation.

      Blangy A.

      Med Sci (Paris) 31:584-6 Pubmed

    • 2014

      The mineral dissolution function of osteoclasts is dispensable for hypertrophic cartilage degradation during long bone development and growth.

      Touaitahuata H, Cres G, de Rossi S, Vives V, Blangy A.

      Dev Biol. 393:57-70. Pubmed

    • 2014

      Modulation of osteoclast differentiation and bone resorption by Rho GTPases.

      Touaitahuata H, Blangy A, Vives V.

      Small GTPases. 5:e28119. Pubmed

    • 2014

      A receptor-interacting protein 1 (RIP1)-independent necrotic death under the control of protein phosphatase PP2A that involves the reorganization of actin cytoskeleton and the action of cofilin-1.

      Tomasella A, Blangy A, Brancolini C.

      J Biol Chem. 289:25699-25710. Pubmed

    • 2014

      Podosome organization drives osteoclast-mediated bone resorption.

      Georgess D, Machuca-Gayet I, Blangy A, Jurdic P.

      Cell Adh Migr. 8:191-204. Pubmed

    • 2014

      Dock-family exchange factors in cell migration and disease.

      Gadea G, Blangy A.

      Eur J Cell Biol. 93:466-77. Pubmed

    • 2014

      Promyelocytic leukemia zinc-finger induction signs mesenchymal stem cell commitment: identification of a key marker for stemness maintenance?

      Djouad F, Tejedor G, Toupet K, Maumus M, Bony C, Blangy A, Chuchana P, Jorgensen C, Noël D.

      Stem Cell Res Ther. 5:27. Pubmed

    • 2013

      Targeting the Dbl and dock-family RhoGEFs: a yeast-based assay to identify cell-active inhibitors of Rho-controlled pathways.

      Blangy A, Fort P.

      Enzymes. 2013;33 Pt A:169-91. Pubmed

    • 2013

      Podosomes are dispensable for osteoclast differentiation and migration.

      Touaitahuata H, Planus E, Albiges-Rizo C, Blangy A, Pawlak G.

      Eur J Cell Biol. 92 : 139-49. Pubmed

    • 2012

      Cofilin activation during podosome belt formation in osteoclasts.

      Blangy A, Touaitahuata H, Cres G, Pawlak G.

      PLoS One. 2012;7(9):e45909. Pubmed

    • 2012

      Using a modified yeast two-hybrid system to screen for chemical GEF inhibitors.

      Blangy A, Fort P.

      Methods Mol Biol. 2012;928:81-95. Pubmed

    • 2011

      The Rac1 exchange factor Dock5 is essential for bone resorption by osteoclasts.

      Vives V, Laurin M, Cres G, Larrousse P, Morichaud Z, Noel D, Côté JF, Blangy A.

      J Bone Miner Res. 2011 May;26(5):1099-110. Pubmed

    • 2008

      RhoE controls myoblast alignment prior fusion through RhoA and ROCK.

      Fortier M, Comunale F, Kucharczak J, Blangy A, Charrasse S, Gauthier-Rouvière C.

      Cell Death Differ. 15(8):1221-31. Pubmed

    To study bone degradation by osteoclasts and its regulation by the signalling pathways controlling the cytoskeleton, we use different approaches:

    – we study the osteoclasts and their bone resorption activity in culture. This allows us to analyse their adhesion structures by fluorescence microscopy and to follow their dynamics by video microscopy. Particularly, we study the different signalling pathways that affect the cytoskeleton of osteoclasts and how they impact on their ability to degrade bone.

    – we also study the bone tissue dynamics in different mouse models. We use mice in which genes of interest have been invalidated or mouse models of bone diseases, such as postmenopausal osteoporosis, rheumatoid arthritis or bone metastases. We perform histo-morphometric and micro-tomographic analyses to understand how the osteoclast cytoskeleton dynamics influences the bony skeleton normal and pathological dynamics.

    – we develop new inhibitors of bone resorption that target the molecular mechanisms we have identified.