title: Pharmacological inhibition of Dock5 prevents osteolysis by affecting osteoclast podosome organization while preserving bone formation.
abstract: Osteoporosis is caused by excessive activity of bone-degrading osteoclasts over bone-forming osteoblast. Standard antiosteolytic treatments inhibit bone resorption by inducing osteoclast loss, with the adverse effect of hindering also bone formation. Formation of the osteoclast sealing zone requires Dock5, a guanine nucleotide exchange factor for the small GTPase Rac, and C21, a chemical inhibitor of Dock5, decreases bone resorption by cultured osteoclasts. Here we show that C21 directly inhibits the exchange activity of Dock5 and disrupts osteoclast podosome organization. Remarkably, C21 administration protects mice against bone degradation in models recapitulating major osteolytic diseases: menopause, rheumatoid arthritis and bone metastasis. Furthermore, C21 administration does not affect bone formation and is not toxic. Our results validate the pharmacological inhibition of Dock5 as a novel therapeutic route for fighting osteolytic diseases while preserving bone formation.
authors: 1] Centre de Recherche de Biochimie Macromoléculaire, CNRS UMR 5237, 34293, Montpellier cedex 5, France [2] Montpellier University, 34095 Montpellier cedex 5, France.
authors: Virginie
authors: V
authors: Vives
authors: 1] Centre de Recherche de Biochimie Macromoléculaire, CNRS UMR 5237, 34293, Montpellier cedex 5, France [2] Montpellier University, 34095 Montpellier cedex 5, France.
authors: Gaëlle
authors: G
authors: Cres
authors: 1] Centre de Recherche de Biochimie Macromoléculaire, CNRS UMR 5237, 34293, Montpellier cedex 5, France [2] Montpellier University, 34095 Montpellier cedex 5, France.
authors: Christian
authors: C
authors: Richard
authors: Institut de Recherche en Cancérologie de Montpellier, U896 INSERM, 34298 Montpellier cedex 5, France.
authors: Muriel
authors: M
authors: Busson
authors: Laboratoire d'Enzymologie et Biochimie Structurales, CNRS, Centre de Recherche de Gif, 91198 Gif-sur-Yvette, France.
authors: Yann
authors: Y
authors: Ferrandez
authors: Laboratoire d'Enzymologie et Biochimie Structurales, CNRS, Centre de Recherche de Gif, 91198 Gif-sur-Yvette, France.
authors: Anne-Gaelle
authors: AG
authors: Planson
authors: Laboratoire d'Enzymologie et Biochimie Structurales, CNRS, Centre de Recherche de Gif, 91198 Gif-sur-Yvette, France.
authors: Mahel
authors: M
authors: Zeghouf
authors: Laboratoire d'Enzymologie et Biochimie Structurales, CNRS, Centre de Recherche de Gif, 91198 Gif-sur-Yvette, France.
authors: Jacqueline
authors: J
authors: Cherfils
authors: INSERM U1059, Université Jean Monnet, 42023 Saint-Etienne cedex 02, France.
authors: Luc
authors: L
authors: Malaval
authors: 1] Centre de Recherche de Biochimie Macromoléculaire, CNRS UMR 5237, 34293, Montpellier cedex 5, France [2] Montpellier University, 34095 Montpellier cedex 5, France.
authors: Anne
authors: A
authors: Blangy
mesh_terms: D000818:Animals; D001168:Arthritis / Q000139:chemically induced / Q000188:drug therapy; D005260:Female; D020662:Guanine Nucleotide Exchange Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010010:Osteoclasts / Q000187:drug effects* / Q000378:metabolism*; D010012:Osteogenesis / Q000187:drug effects*; D010014:Osteolysis / Q000188:drug therapy*; D010024:Osteoporosis / Q000139:chemically induced / Q000188:drug therapy; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D000096926:Benzenesulfonamides
chemical_list: D020662:Guanine Nucleotide Exchange Factors; D013449:Sulfonamides; D000096926:Benzenesulfonamides; C531318:Dock5 protein, mouse