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

Virginie Vives,Anne Blangy,Christian Richard,Jacqueline Cherfils,Muriel Busson,Gaëlle Cres,Luc Malaval,Anne-Gaelle Planson,Mahel Zeghouf,Yann Ferrandez

doi:10.1038/ncomms7218

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.

Highlights

Osteoporosis is caused by excessive activity of bone-degrading osteoclasts over bone-forming osteoblast
The most widely used antiosteolytic treatments are nitrogen-containing bisphosphonates, which induce osteoclast apoptosis, and denosumab, a humanized monoclonal antibody to RANKL that inhibits osteoclast differentiation
An important issue with those treatments is that they strongly affect bone formation[2]. This is suspected to contribute to clinical complications such as atypical subtrochanteric femur fractures and osteonecrosis of the jaw and reduce responsiveness to the bone anabolic factor parathyroid hormone[3,4,5]

Summary

Introduction

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 bone formation. We identified C21, a chemical compound blocking Rac activation by Dock[5] in cultured cells that inhibits bone degradation by osteoclasts in vitro[11]. The aim of the present study was to use this compound as a model to test whether targeting the osteoclast podosome patterning via the pharmacological inhibition of Dock[5] could prevent pathological bone loss while preserving bone formation. Using three mouse models for the most common osteolytic diseases, we show here that systemic administration of the inhibitor of Dock[5] efficiently prevents pathological bone loss while preserving bone formation

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