M-CSF Regulates the Cytoskeleton via Recruitment of a Multimeric Signaling Complex to c-Fms Tyr-559/697/721

Faccio, Roberta; Takeshita, Satoshi; Colaianni, Graziana; Chappel, Jean; Zallone, Alberta; Teitelbaum, Steven L.; Ross, F. Patrick

doi:10.1074/jbc.m610937200

Cited by 48 publications

(57 citation statements)

References 61 publications

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“…M-CSF is known to stimulate osteoclast migration and it has been proposed that this is associated with the disassembly of the resorption machinery. 32 We found that M-CSF alone did not inhibit the resorption activity of osteoclasts derived from most GCTBs. In fact, a stimulatory effect on resorption was seen in a minority of GCTBs, which clinically and morphologically were not obviously different from other (unstimulated) GCTBs.…”

Section: Osteoclastogenesis By M-csf Substitutes Rm Taylor Et Almentioning

confidence: 66%

VEGF, FLT3 ligand, PlGF and HGF can substitute for M-CSF to induce human osteoclast formation: implications for giant cell tumour pathobiology

Taylor

Kashima

Knowles

et al. 2012

Laboratory Investigation

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Giant cell tumour of bone (GCTB) is a primary bone tumour that contains numerous very large, hyper-nucleated osteoclastic giant cells. Osteoclasts form from CD14 þ monocytes and macrophages in the presence of receptor activator of nuclear factor kappa B ligand (RANKL) and macrophage-colony stimulating factor (M-CSF). GCTB contains numerous growth factors, some of which have been reported to influence osteoclastogenesis and resorption. We investigated whether these growth factors are capable of substituting for M-CSF to support osteoclast formation from cultured human monocytes and whether they influence osteoclast cytomorphology and resorption. Vascular endothelial growth factor-A (VEGF-A), VEGF-D, FLT3 ligand (FL), placental growth factor (PlGF) and hepatocyte growth factor (HGF) supported RANKL-induced osteoclastogenesis in the absence of M-CSF, resulting in the formation of numerous TRAP þ multinucleated cells capable of lacunar resorption. Monocytes cultured in the presence of M-CSF, HGF, VEGF-A and RANKL together resulted in the formation of very large, hyper-nucleated (GCTB-like) osteoclasts that were hyper-resorptive. M-CSF and M-CSF substitute growth factors were identified immunohistochemically in GCTB tissue sections and these factors stimulated the resorption of osteoclasts derived from a subset of GCTBs. Our findings indicate that there are growth factors that are capable of substituting for M-CSF to induce human osteoclast formation and that these factors are present in GCTB where they influence osteoclast cytomorphology and have a role in osteoclast formation and resorption activity. The osteoclast is a multinucleated cell, which is formed from circulating mononuclear phagocyte precursors derived from the bone marrow. 1,2 It exhibits a number of specialised cytochemical and functional features, including the ability to carry out lacunar bone resorption. Increased osteoclast formation and activity is seen in a number of osteolytic bone and joint conditions, including notably giant cell tumour of bone (GCTB), a primary bone tumour, which contains numerous, very large, often hyper-nucleated osteoclastic giant cells that effect a considerable amount of bone resorption. 3,4 Osteoclast differentiation from monocyte or macrophage precursors requires the presence of receptor activator of nuclear factor kappa B ligand (RANKL) and macrophage-colony stimulating factor (M-CSF). 5 The importance of M-CSF in osteoclast formation is evidenced by the fact that in op/op osteopetrotic mice, which have a mutation in the M-CSF gene, very few osteoclasts are found in bone and there is markedly decreased bone resorption. 6,7 M-CSF promotes several aspects of osteoclastogenesis including the proliferation and fusion of osteoclast precursors as well as osteoclasts and the expression of the RANKL receptor by these cells. [8][9][10] The effect of M-CSF on mature osteoclast resorption activity is controversial with both a decrease and increase in lacunar resorption being reported. [11][12][13] Although bone resorption is gre...

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Section: Osteoclastogenesis By M-csf Substitutes Rm Taylor Et Almentioning

confidence: 66%

VEGF, FLT3 ligand, PlGF and HGF can substitute for M-CSF to induce human osteoclast formation: implications for giant cell tumour pathobiology

Taylor

Kashima

Knowles

et al. 2012

Laboratory Investigation

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“…(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%

“…M-CSF regulates OC cytoskeleton (28) and induces rapid activation of Rac1, leading to the phosphorylation of Erk1/2. (29,30) Integrin avb3 stimulation by adhesion of OCs onto vitronectin also activates Rac1.…”

Section: Dock5 Is Necessary For Rac1 and P130cas Activation In Ocsmentioning

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

108

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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“…c-Src is specifically recruited to the terminal 3 aa of the ␤3 subunit of the ␣v␤3 integrin (7) and to Y559 of the macrophage-colony stimulating factor (M-CSF) receptor (8), c-Fms, to modulate cytoskeletal changes. It also binds to activated RANK (9), thereby recruiting TRAF6 and Grb2-associated binder 2 (Gab2) followed by phosphorylation of I B␣ and JNK (10), which ultimately lead to respective activation of the transcription factors NF-B and AP-1 (2,11,12).…”

mentioning

confidence: 99%