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

Virginie Vives, Gaëlle Cres, Christian Richard, Muriel Busson, Yann Ferrandez, Anne-Gaelle Planson, Mahel Zeghouf, Jacqueline Cherfils, Luc Malaval and Anne Blangy ()
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Virginie Vives: Centre de Recherche de Biochimie Macromoléculaire, CNRS UMR 5237, 34293
Gaëlle Cres: Centre de Recherche de Biochimie Macromoléculaire, CNRS UMR 5237, 34293
Christian Richard: Centre de Recherche de Biochimie Macromoléculaire, CNRS UMR 5237, 34293
Muriel Busson: Institut de Recherche en Cancérologie de Montpellier
Yann Ferrandez: Laboratoire d’Enzymologie et Biochimie Structurales, CNRS, Centre de Recherche de Gif
Anne-Gaelle Planson: Laboratoire d’Enzymologie et Biochimie Structurales, CNRS, Centre de Recherche de Gif
Mahel Zeghouf: Laboratoire d’Enzymologie et Biochimie Structurales, CNRS, Centre de Recherche de Gif
Jacqueline Cherfils: Laboratoire d’Enzymologie et Biochimie Structurales, CNRS, Centre de Recherche de Gif
Luc Malaval: INSERM U1059, Université Jean Monnet, 42023
Anne Blangy: Centre de Recherche de Biochimie Macromoléculaire, CNRS UMR 5237, 34293

Nature Communications, 2015, vol. 6, issue 1, 1-9

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms7218

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