Deleting Rac1 improves vertebral bone quality and resistance to fracture in a murine ovariectomy model

Magalhaes, Joyce; Grynpas, Marc D.; Willett, Thomas L.; Glogauer, Michael

doi:10.1007/s00198-010-1355-6

Cited by 16 publications

(13 citation statements)

References 43 publications

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“…13 Although the results are somehow conflicting and their precise function not elucidated yet, both Rac1 and Rac2 seem to be important for the formation of the podosome belt and for bone resorption. 31,[63][64][65][66] This confirms earlier studies showing podosome belt disruption in osteoclasts where Rac1 and Rac2 have been neutralized by specific antibodies. 67 Using DNA microarray, we analyzed the expression profile of 76 GEFs of the Dbl and Dock families in osteoclasts.…”

Section: Adhesion Structuressupporting

confidence: 88%

“…Although the authors agree on the increase in bone density, there are discrepancies regarding the mechanisms involved that will need further investigation. 31,[63][64][65] Interestingly, the absence of a single Rac GEF, such as Vav3, Dock5 or FARP2, is sufficient to result in osteoclasts impaired resorption in vivo, through distinct mechanisms. [68][69][70] The higher bone density observed in mice deficient for Rho GTPase signaling highlights them as targets in diseases with increased bone resorption such as post-menopausal osteoporosis or cancer-associated osteolysis.…”

Section: Resultsmentioning

confidence: 99%

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Modulation of osteoclast differentiation and bone resorption by Rho GTPases

2014

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Section: Adhesion Structuressupporting

confidence: 88%

Section: Resultsmentioning

confidence: 99%

Modulation of osteoclast differentiation and bone resorption by Rho GTPases

2014

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“…During osteoclast resorption cycle, αvβ3 integrins signalling induces Dock5 recruitment to the Src/Pyk2/p130Cas complex which ultimately leads to Rac1 activation and localisation to the sealing zone [Vives et al., ]. Dock5 plays an important role in this pathway because its deletion in knockout mice results in increased trabecular bone mass due to an impaired osteoclasts ability to assemble podosomes into sealing zones [Vives et al., ], a phenotype also observed in knockout mice for Rac1 [Croke et al., ; Magalhaes et al., ] and some of its guanine exchange factors [Faccio et al., ; Takegahara et al., ]. Interestingly, a group working on allergy showed that Dock5 is essential for the dynamic rearrangement of microtubules during mast cell degranulation in anaphylactic responses [Ogawa et al., ].…”

Section: Introductionmentioning

confidence: 99%

Dock5 is a new regulator of microtubule dynamic instability in osteoclasts

Guimbal

Morel

Guérit

et al. 2019

Biology of the Cell

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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.

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“…During osteoclast resorption cycle, αvβ3 integrins signaling induces Dock5 recruitment to the Src/Pyk2/p130Cas complex which (Nagai et al, 2013). Dock5 plays an important role in this pathway because its deletion in knockout mice results in increased trabecular bone mass due to an impaired osteoclasts ability to assemble podosomes into sealing zones (Vives et al, 2011), a phenotype also observed in knockout mice for Rac1 (Croke et al, 2011) (Magalhaes et al, 2011 and its guanine exchange factors (Faccio et al, 2005) (Takegahara et al, 2010. Interestingly, a group working on allergy showed that Dock5 is essential for the dynamic rearrangement of microtubules during mast cell degranulation in anaphylactic responses (Ogawa et al, 2014).…”

mentioning

confidence: 99%

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

Guimbal

Guérit

et al. 2019

Preprint

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Background information:Osteoclast 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. 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 polymerized tubulin but through inhibition of the microtubules destabilizing kinase GSK3β downstream of Akt activation.Interestingly, we ruled out the implication of Rac1 in this process using specific inhibitors. Conclusion:Our data involve Dock5 as a new regulator of microtubule dynamic instability in osteoclast. Significance:The 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.

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Deleting Rac1 improves vertebral bone quality and resistance to fracture in a murine ovariectomy model

Abstract: Our results demonstrate that the deletion of Rac1 increases vertebral bone quality compared to WT bones in a postmenopausal osteoporosis model.

Cited by 16 publications

References 43 publications

Modulation of osteoclast differentiation and bone resorption by Rho GTPases

Modulation of osteoclast differentiation and bone resorption by Rho GTPases

Dock5 is a new regulator of microtubule dynamic instability in osteoclasts

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

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