Activated c-Fms recruits Vav and Rac during CSF-1-induced cytoskeletal remodeling and spreading in osteoclasts

Sakai, Hiroaki; Chen, Yan; Itokawa, Takashi; Yu, Kuan-Ping; Zhu, Meiling; Insogna, Karl L.

doi:10.1016/j.bone.2006.06.012

Cited by 45 publications

(58 citation statements)

References 50 publications

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“…17-AAG potentiates and prolongs the Src kinase activity induced by M-CSF alone, and a neutralizing antibody to M-CSF blocks 17-AAG-induced Src activation. In the osteoclast maturation program, M-CSF is required for Src-dependent cytoskeletal reorganization, during which Src associates with and phosphorylates integrin ␤3 (30,33). Here, we demonstrate that 17-AAG and M-CSF synergistically activate Src-mediated integrin ␤3 phosphorylation (31,33).…”

Section: Discussionmentioning

confidence: 62%

“…The M-CSF receptor, c-Fms, is highly expressed on mature osteoclasts (28), and interaction of M-CSF with c-Fms promotes actin reorganization and cell spreading. Src is likely to be required in this pathway because the ability of M-CSF to modulate cytoskeleton reorganization is not observed in osteoclasts derived from src Ϫ/Ϫ mice, and M-CSF induces Src-dependent tyrosine phosphorylation in osteoclasts (29,30). To investigate the possible impact of 17-AAG on this signaling pathway, we first examined the effect of 17-AAG on M-CSF-induced Src activation.…”

Section: -Aag Prolongs M-csf-induced Src Kinase Activation and Potementioning

confidence: 99%

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Inhibition of Hsp90 activates osteoclast c-Src signaling and promotes growth of prostate carcinoma cells in bone

Yano

Tsutsumi

Soga

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Hsp90 inhibitors are being evaluated extensively in patients with advanced cancers. However, the impact of Hsp90 inhibition on signaling pathways in normal tissues and the effect that this may have on the antitumor activity of these molecularly targeted drugs have not been rigorously examined. Breast and prostate carcinomas are among those cancers that respond to Hsp90 inhibitors in animal xenograft models and in early studies in patients. Because these cancers frequently metastasize to bone, it is important to determine the impact of Hsp90 inhibitors in the bone environment. In the current study, we show that, in contrast to its activity against prostate cancer cells in vitro and its inhibition of s.c. prostate cancer xenografts, the Hsp90 inhibitor 17-AAG stimulates the intraosseous growth of PC-3M prostate carcinoma cells. This activity is mediated not by a direct effect on the tumor but by Hsp90-dependent stimulation of osteoclast maturation. Hsp90 inhibition transiently activates osteoclast Src kinase and promotes Srcdependent Akt activation. Both kinases are key drivers of osteoclast maturation, and three agents that block osteoclastogenesis, the Src inhibitor dasatinib, the bisphosphonate alendronate, and the osteoclast-specific apoptosis-inducer reveromycin A, markedly reduced 17-AAG-stimulated tumor growth in bone. These data emphasize the importance of understanding the complex role played by Hsp90 in regulating signal transduction pathways in normal tissues as well as in cancer cells, and they demonstrate that drug-dependent modulation of the local tumor environment may profoundly affect the antitumor efficacy of Hsp90-directed therapy.cancer ͉ geldanamycin ͉ heat shock protein 90 ͉ osteoclastogenesis

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Section: Discussionmentioning

confidence: 62%

Section: -Aag Prolongs M-csf-induced Src Kinase Activation and Potementioning

confidence: 99%

Inhibition of Hsp90 activates osteoclast c-Src signaling and promotes growth of prostate carcinoma cells in bone

Yano

Tsutsumi

Soga

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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“…M-CSF and adhesion were shown to activate Vav3, which is then recruited with Rac1 at the plasma membranes of OCs. (49) We found that Dock5 associates with the OC podosome belt. A possible hypothesis would be that Dock5 and Vav3 regulate Rac1 activation at distinct locations in OCs and at different phases of the bone-resorption cycle (Fig.…”

Section: Discussionmentioning

confidence: 72%

“…(7) After the end of a resorption step, activation of c-Fms by M-CSF and of integrins through adhesion would recruit and activate Vav3 at the plasma membrane, leading to rapid activation of Rac1. (28,49) This would allow the OC spreading and actin remodeling necessary for the initiation of new sealing zone formation (Fig. 7B).…”

Section: Discussionmentioning

confidence: 99%

The Rac1 exchange factor Dock5 is essential for bone resorption by osteoclasts

Vives

Laurin

Crès

et al. 2010

Journal of Bone and Mineral Research

106

148

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Osteoporosis, which results from excessive bone resorption by osteoclasts, is the major cause of morbidity for elder people. Identification of clinically relevant regulators is needed to develop novel therapeutic strategies. Rho GTPases have essential functions in osteoclasts by regulating actin dynamics. This is of particular importance because actin cytoskeleton is essential to generate the sealing zone, an osteoclast-specific structure ultimately mediating bone resorption. Here we report that the atypical Rac1 exchange factor Dock5 is necessary for osteoclast function both in vitro and in vivo. We discovered that establishment of the sealing zone and consequently osteoclast resorbing activity in vitro require Dock5. Mechanistically, our results suggest that osteoclasts lacking Dock5 have impaired adhesion that can be explained by perturbed Rac1 and p130Cas activities. Consistent with these functional assays, we identified a novel small-molecule inhibitor of Dock5 capable of hindering osteoclast resorbing activity. To investigate the in vivo relevance of these findings, we studied Dock5 -/-mice and found that they have increased trabecular bone mass with normal osteoclast numbers, confirming that Dock5 is essential for bone resorption but not for osteoclast differentiation. Taken together, our findings characterize Dock5 as a regulator of osteoclast function and as a potential novel target to develop antiosteoporotic treatments. ß

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“…However, the positive effect of autocrine chemoattractant receptor signaling in OCP differentiation is likely an artifact of in vitro culture conditions because in these conditions OCPs are not exposed to other chemoattractants secreted by BM cells. In vivo, our findings suggest that autocrine EBI2 signaling attenuates the sensing of EBI2 RAC2 contribution in OC differentiation in vivo (using a similar genetic approach) and failed to detect significant roles in OC differentiation in vivo, but reported a dramatic RAC dependency in OCs for bone resorption (Croke et al, 2011), presumably caused by defective CSF1R signaling (Sakai et al, 2006). Although other chemoattractant receptors are likely involved in promoting OCP motility and directed cells can still migrate toward bone surfaces and differentiate into multinucleated mature OCs, albeit less efficiently.…”

Section: Discussionmentioning

confidence: 84%

Oxysterols and EBI2 promote osteoclast precursor migration to bone surfaces and regulate bone mass homeostasis

Nevius¹,

Pinho²,

Dhodapkar³

et al. 2015

J Cell Biol

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Bone surfaces attract hematopoietic and nonhematopoietic cells, such as osteoclasts (OCs) and osteoblasts (OBs), and are targeted by bone metastatic cancers. However, the mechanisms guiding cells toward bone surfaces are essentially unknown. Here, we show that the Gi protein-coupled receptor (GPCR) EBI2 is expressed in mouse monocyte/OC precursors (OCPs) and its oxysterol ligand 7,25-dihydroxycholesterol (7,25-OHC) is secreted abundantly by OBs. Using in vitro time-lapse microscopy and intravital two-photon microscopy, we show that EBI2 enhances the development of large OCs by promoting OCP motility, thus facilitating cell-cell interactions and fusion in vitro and in vivo. EBI2 is also necessary and sufficient for guiding OCPs toward bone surfaces. Interestingly, OCPs also secrete 7,25-OHC, which promotes autocrine EBI2 signaling and reduces OCP migration toward bone surfaces in vivo. Defective EBI2 signaling led to increased bone mass in male mice and protected female mice from age-and estrogen deficiency-induced osteoporosis. This study identifies a novel pathway involved in OCP homing to the bone surface that may have significant therapeutic potential.

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Activated c-Fms recruits Vav and Rac during CSF-1-induced cytoskeletal remodeling and spreading in osteoclasts

Cited by 45 publications

References 50 publications

Inhibition of Hsp90 activates osteoclast c-Src signaling and promotes growth of prostate carcinoma cells in bone

Inhibition of Hsp90 activates osteoclast c-Src signaling and promotes growth of prostate carcinoma cells in bone

The Rac1 exchange factor Dock5 is essential for bone resorption by osteoclasts

Oxysterols and EBI2 promote osteoclast precursor migration to bone surfaces and regulate bone mass homeostasis

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