Dock5 is a new regulator of microtubule dynamic instability through GSK3β inhibition in osteoclasts

Abstract

Background informationOsteoclast resorption is dependent on a podosome-rich structure, called sealing zone, which is stabilized by acetylated microtubules. It tightly attaches the osteoclast to the bone creating a favorable acidic microenvironment for bone degradation. We already established that Rac activation by Dock5 is necessary for osteoclast resorption. Indeed, inhibition of Dock5 in osteoclasts results in Rac1 decreased activity associated to impaired podosome assembly into sealing zones and resorbing activity.\n\nResultsIn this report, we show that Dock5 knockout osteoclasts also present a reduced acetylated tubulin level leading to a decreased length and duration of microtubule growth phases whereas their growth speed remains unaffected. Dock5 does not act by direct interaction with the polymerized tubulin but through inhibition of the microtubules destabilizing kinase GSK3{beta} downstream of Akt activation. Interestingly, we ruled out the implication of Rac1 in this process using specific inhibitors.\n\nConclusionOur data involve Dock5 as a new regulator of microtubule dynamic instability in osteoclast.\n\nSignificanceThe fact that Dock5 is a regulator of both actin cytoskeleton and microtubule dynamics makes it an interesting therapeutic target for osteolytic pathologies because of its dual role on sealing zone formation and stabilization.