Dock5 is a new regulator of microtubule dynamic instability in osteoclasts

Abstract

Background Information. Osteoclast resorption is dependent on a podosome-rich structure called sealing zone. It tightly attaches the osteoclast to the bone creating a favourable acidic microenvironment for bone degradation. This adhesion structure needs to be stabilised by microtubules whose acetylation is maintained by down-regulation of deacetylase HDAC6 and/or of microtubule destabilising kinase GSK3β activities. We already established that Dock5 is a guanine nucleotide exchange factor for Rac1. As a consequence, Dock5 inhibition results in a decrease of the GTPase activity associated with impaired podosome assembly into sealing zones and resorbing activity in osteoclasts. More, administration of C21, a chemical compound that directly inhibits the exchange activity of Dock5, disrupts osteoclast podosome organisation and protects mice against bone degradation in models recapitulating major osteolytic diseases.Results. In 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 polymerised tubulin. Using specific Rac inhibitors, we showed that Dock5 regulates microtubule dynamic instability through Rac-dependent and -independent pathways. The latter involves GSK3β inhibitory serine 9 phosphorylation downstream of Akt activation but not HDAC6 activity.Conclusion. We showed that Dock5 is a new regulator of microtubule dynamic instability in osteoclast.Significance. Dock5 dual role in the regulation of the actin cytoskeleton and microtubule, which both need to be intact for bone resorption, reinforces the fact that it is an interesting therapeutic target for osteolytic pathologies.

AKAP6 orchestrates the nuclear envelope microtubule-organizing center by linking golgi and nucleus via AKAP9

“…Previously, it has been shown that the Golgi and/or microtubules play an important role in cardiomyocyte cell growth (hypertrophy) ( Nash et al, 2019 ) and bone resorption activity of osteoclast ( Guimbal et al, 2019 ; Ng et al, 2013 ; Ye et al, 2011 ). Therefore, we tested whether AKAP6 is required for these cellular functions.…”

The osteoclast cytoskeleton – current understanding and therapeutic perspectives for osteoporosis

“…Thus, Arap1 couples the regulation of actin through its RhoA GAP domain to that of membrane trafficking to the ruffled border through its Arf GAP domain (Segeletz et al, 2018). Similarly, Dock5 is likely to participate in actin and microtubule crosstalk as this GEF for Rac also controls microtubule dynamics and acetylation in osteoclasts (Guimbal et al, 2019), as detailed below.…”

“…2). In the absence of DOCK5, GSK3β activity increases and microtubules acetylation is reduced, with a concomitant reduction in the length and duration of microtubule growth (Guimbal et al, 2019).…”

The role of Rho GTPases’ substrates Rac and Cdc42 in osteoclastogenesis and relevant natural medicinal products study

“…These results speculated that Rac1 and Rac2 might function in osteoclastic organelle actin dynamics regulating, such as: actin filament ends and podosomes. In fact, Rac1 and Rac2 proteins have overlapping roles in podosome assembly and SZL formation by localizing Arp2/3 at podosome sites during osteoclastogenesis [7,[21][22][23][24][25][26][27]. Osteoclasts generated from the Rac1 and Rac2 double knockout mouse are devoid of podosomes and SZ, which finally showed impaired bone resorption capacities [24,[28][29][30][31][32].…”