Bone Abstracts

Molecules secreted by the osteoclast or ‘clastokynes’ are essential to stimulate bone formation by osteoblasts. Treatments with bisphosphates and Denosumab target osteoclast survival and differentiation. This suppresses bone turnover and is suspected to increase the risk of atypical fractures in the long term. A solution to overcome this is to develop strategies that target selectively the activity of osteoclasts without affecting their survival or differentiation. So far, this relies on the development of Cathepsin K inhibitors that do prevent osteoclast activity and preserve bone formation.

Here we propose the alternative solution to specifically target the organization of podosomes in osteoclasts. Preventing sealing zone formation by affecting the patterning of podosomes impairs the acidification of the extracellular medium by osteoclasts, which renders bone resorption ineffective. We reported earlier that Dock5 controls podosome patterning for sealing zone formation and the development of a chemical compound C21 that inhibits the activation of the GTPase Rac by Dock5. C21 prevents bone degradation by osteoclasts in culture (Vives et al. JBMR, 2011).

We used C21 to test if targeting podosome organization in osteoclasts could prevent osteolysis in vivo. We show that C21 indeed destabilizes podosomes organization rapidly and reversibly, in cultured osteoclasts. We further report that administration of C21 efficiently protects mice against bone loss, using established mouse models of post menopause osteoporosis, rheumatoid arthritis and bone metastases. C21 had no noticeable adverse effect in the mouse. Most interestingly, bone formation parameters (MS/BS, MAR and BFR/BS) are not affected by C21, while they are severely diminished in mice treated with Alendronate.

Our results provide the proof of concept that a chemical compound that destabilizes podosome organization in osteoclasts efficiently protects against pathological bone loss without affecting bone formation. Our findings open new avenues to develop innovative strategies for the treatment of osteolytic bone diseases.