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 & Anne Blangy


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 ock5, a guanine nucleotide exchange factor for the small GTPase Rac, and 21, a chemical inhibitor of ock5, decreases bone resorption by cultured osteoclasts. Here we show that 21 directly inhibits the exchange activity of ock5 and disrupts osteoclast podosome organization. Remarkably, 21 administration protects mice against bone degradation in models recapitulating major osteolytic diseases: menopause, rheumatoid arthritis and bone metastasis. Furthermore, 21 administration does not affect bone formation and is not toxic. Our results validate the pharmacological inhibition of ock5 as a novel therapeutic route for fighting osteolytic diseases while preserving bone formation.

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