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

• Published in: Nature communications 2015-02, Vol.6 (1), p.6218, Article 6218
• Main Authors: Vives, Virginie, Cres, Gaëlle, Richard, Christian, Busson, Muriel, Ferrandez, Yann, Planson, Anne-Gaelle, Zeghouf, Mahel, Cherfils, Jacqueline, Malaval, Luc, Blangy, Anne
• Format: Article
• Language: English
• Subjects: 13; 14; 59; 59/5; 64/60; 692/308; 692/698/690/797; 692/699/2743/316/801; 692/700/565/1436; 82; 96; Animals; Arthritis - chemically induced; Arthritis - drug therapy; Benzenesulfonamides; Biochemistry, Molecular Biology; Biophysics; Cellular Biology; Female; Guanine Nucleotide Exchange Factors - antagonists & inhibitors; Guanine Nucleotide Exchange Factors - metabolism; Humanities and Social Sciences; Life Sciences; Male; Metastasis; Mice; Mice, Inbred C57BL; multidisciplinary; Osteoclasts - drug effects; Osteoclasts - metabolism; Osteogenesis - drug effects; Osteolysis - drug therapy; Osteoporosis; Osteoporosis - chemically induced; Osteoporosis - drug therapy; Science; Science (multidisciplinary); Sulfonamides - chemistry; Sulfonamides - pharmacology; Sulfonamides - therapeutic use; Toxicity
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms7218

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. Small-molecule C21 inhibits Rac GTPase activation by Dock5, which decreases osteoclast activity in vitro . Using three mouse models where bone loss is caused by hyperactive osteoclasts, Vives et al . show that C21 treatment safely and efficiently prevents osteoporosis while preserving bone formation.