Colony-stimulating factor 1 receptor inhibition prevents against lipopolysaccharide -induced osteoporosis by inhibiting osteoclast formation

IL-33 is an important inflammatory mediator in allergy, asthma, and joint inflammation, acting via its receptor, ST2L, to elicit Th2 cell cytokine secretion. IL-33 is related to IL-1 and IL-18, which both influence bone metabolism, IL-18 in particular inhibiting osteoclast formation and contributing to PTH bone anabolic actions. We found IL-33 immunostaining in osteoblasts in mouse bone and IL-33 mRNA expression in cultured calvarial osteoblasts, which was elevated by treatment with the bone anabolic factors oncostatin M and PTH. IL-33 treatment strongly inhibited osteoclast formation in bone marrow and spleen cell cultures but had no effect on osteoclast formation in receptor activator of nuclear factor-κB ligand/macrophage colony-stimulating factor-treated bone marrow macrophage (BMM) or RAW264.7 cultures, suggesting a lack of direct action on immature osteoclast progenitors. However, osteoclast formation from BMM was inhibited by IL-33 in the presence of osteoblasts, T cells, or mature macrophages, suggesting these cell types may mediate some actions of IL-33. In bone marrow cultures, IL-33 induced mRNA expression of granulocyte macrophage colony-stimulating factor, IL-4, IL-13, and IL-10; osteoclast inhibitory actions of IL-33 were rescued only by combined antibody ablation of these factors. In contrast to osteoclasts, IL-33 promoted matrix mineral deposition by long-term ascorbate treated primary osteoblasts and reduced sclerostin mRNA levels in such cultures after 6 and 24 h of treatment; sclerostin mRNA was also suppressed in IL-33-treated calvarial organ cultures. In summary, IL-33 stimulates osteoblastic function in vitro but inhibits osteoclast formation through at least three separate mechanisms. Autocrine and paracrine actions of osteoblast IL-33 may thus influence bone metabolism.

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Influence of receptor activator of nuclear factor (NF)-kB ligand (RANKL), macrophage-colony stimulating factor (M-CSF) and fetal calf serum on human osteoclast formation and activity

Journal of Molecular Histology ◽

10.1007/s10735-007-9133-2 ◽

2007 ◽

Vol 38 (5) ◽

pp. 507-512

Author(s):

Ludwika Kreja ◽

Astrid Liedert ◽

Carla Schmidt ◽

Lutz Claes ◽

Anita Ignatius

Keyword(s):

Fetal Calf Serum ◽

Calf Serum ◽

Osteoclast Formation ◽

Nuclear Factor ◽

Colony Stimulating Factor ◽

Receptor Activator ◽

Human Osteoclast ◽

Macrophage Colony Stimulating Factor ◽

Macrophage Colony ◽

Stimulating Factor

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Macrophage colony-stimulating factor induces substantial osteoclast generation and bone resorption in human bone marrow cultures

Blood ◽

10.1182/blood.v88.7.2531.bloodjournal8872531 ◽

1996 ◽

Vol 88 (7) ◽

pp. 2531-2540 ◽

Cited By ~ 81

Author(s):

U Sarma ◽

AM Flanagan

Keyword(s):

Bone Resorption ◽

Vitamin D3 ◽

Osteoclast Formation ◽

Dependent Manner ◽

Colony Stimulating Factor ◽

Macrophage Colony Stimulating Factor ◽

Macrophage Colony ◽

Human Osteoclasts ◽

Stimulating Factor

Macrophage colony-stimulating factor (M-CSF) is essential for murine osteoclast formation and its role in human hematopoiesis in vitro is not fully defined. Therefore, we have investigated the effect of M-CSF on the formation of human osteoclasts in vitro. M-CSF was found to induce substantial bone resorption and osteoclast formation in a dose-responsive and time-dependent manner above that induced by 1,25 dihydroxyvitamin D3 (1,25 vitamin D3) in cultures of human bone marrow (BM) stromal cells sedimented onto devitalized bone. By day 14 there was a mean of approximately 50% of the surfaces of the bone slices resorbed compared with only 6% in cultures treated with 1,25 vitamin D3 alone. Osteoclasts were identified as 23c6+ cells (an antibody that recognizes the vitronectin receptor), 87.5% of which coexpressed the calcitonin receptor. The number of 23c6+ cells correlated strongly with bone resorption spatially, and in a dose-responsive and time-dependent manner; the correlation coefficient in cultures treated with 1,25 vitamin D3 alone was 0.856 and those treated with both M-CSF and 1,25 vitamin D3 was 0.880. Granulocyte-macrophage colony-stimulating factor, IL-1 beta, IL-3, IL-6, tumor necrosis factor-alpha, transforming growth factor-beta, leukemia inhibitory factor, and IL-11 did not increase bone resorption above that in 1,25 vitamin D3-treated cultures. We also found that 1,25 vitamin D3 increased, to a minor but significant degree, both bone resorption and the concentration of M-CSF in the culture supernatants above that in vehicle-treated cultures, indicating that M-CSF is present in our BM cultures, but that there is insufficient to induce substantial osteoclast formation. These results define a critical role for M-CSF in the formation of human osteoclasts.

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Local concentrations of macrophage colony-stimulating factor mediate osteoclastic differentiation

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1995.269.6.e1024 ◽

1995 ◽

Vol 269 (6) ◽

pp. E1024-E1030 ◽

Cited By ~ 2

Author(s):

S. L. Perkins ◽

S. J. Kling

Keyword(s):

Bone Marrow ◽

Osteoclast Differentiation ◽

Osteoclast Formation ◽

Tartrate Resistant Acid Phosphatase ◽

Nonspecific Esterase ◽

Colony Stimulating Factor ◽

Murine Bone Marrow ◽

Macrophage Colony Stimulating Factor ◽

Macrophage Colony ◽

Stimulating Factor

Macrophage colony-stimulating factor (M-CSF) is essential for differentiation of osteoclasts and macrophages from a common bone marrow precursor. Using ST-2 stromal cell/murine bone marrow coculture, we studied the effects of increasing amounts of M-CSF on differentiation of macrophages and osteoclasts. Addition of exogenous M-CSF caused a dose-dependent 98% decrease in tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells, accompanied by a 2.5-fold increase in nonspecific esterase-staining macrophages. Similar decrease in osteoclastic functional activity, including 125I-labeled calcitonin binding and calcitonin-stimulated adenosine 3',5'-cyclic monophosphate (cAMP) production, were observed. Addition of exogenous M-CSF beyond 6 days in coculture had a decreasing ability to inhibit osteoclast formation, suggesting that M-CSF exerts its effects early in osteoclast differentiation, during the proposed proliferative phase of osteoclast formation. Similarly, early addition of neutralizing anti-M-CSF inhibited osteoclast formation, with diminishing effects beyond day 9. These results suggest that local high concentrations of M-CSF may influence the early determination of terminal differentiation into either macrophages or osteoclasts.

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Colony‐stimulating factor‐1 receptor inhibition attenuates microgliosis and myelin loss but exacerbates neurodegeneration in the chronic cuprizone model

Journal of Neurochemistry ◽

10.1111/jnc.15566 ◽

2021 ◽

Author(s):

V.S.B. Wies Mancini ◽

A.A. Di Pietro ◽

S. de Olmos ◽

P.R. Silva ◽

M. Vence ◽

...

Keyword(s):

Colony Stimulating Factor ◽

Receptor Inhibition ◽

Stimulating Factor

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Phosphatidylinositol 3 Kinase/Akt Signal Relay Cooperates with Smad in Bone Morphogenetic Protein-2-Induced Colony Stimulating Factor-1 (CSF-1) Expression and Osteoclast Differentiation

Endocrinology ◽

10.1210/en.2009-0026 ◽

2009 ◽

Vol 150 (11) ◽

pp. 4989-4998 ◽

Cited By ~ 37

Author(s):

Chandi C. Mandal ◽

Goutam Ghosh Choudhury ◽

Nandini Ghosh-Choudhury

Keyword(s):

Binding Protein ◽

Osteoclast Differentiation ◽

Osteoclast Formation ◽

Bone Morphogenetic Protein 2 ◽

Colony Stimulating Factor ◽

Phosphatidylinositol 3 Kinase ◽

Osteoblast Activity ◽

Stimulating Factor ◽

Phosphatidylinositol 3

Murine spleen cells produce mature osteoclasts when cocultured with osteoblastic cells. Colony-stimulating factor (CSF)-1 is the growth factor required for differentiating the monocyte-macrophage precursor cells into preosteoclasts. Bone morphogenic protein (BMP) signaling in osteoblasts regulates bone mass in mice, suggesting a role of BMP in osteoclastogenesis along with osteoblast activity. The intracellular signal transduction cross talk regulating the osteoblastic production of CSF-1 as a mechanism of BMP-induced osteoclastogenesis is described in this report. We have recently described the involvement of Smad 1/5 in BMP-2-induced CSF-1 expression and osteoclast formation. In this study, using the pharmacological inhibitors and the adenovirus (Ad) vectors expressing dominant-negative (DN) phosphatidylinositol 3 kinase (PI3K), the PI3K-signaling inhibitor, phosphatase and tensin homolog deleted in chromosome 10 (PTEN) or DN Akt kinase in the in vitro coculture assay, we show an essential role of the lipid kinase cascade in BMP-2-mediated multinucleated osteoclast formation and CSF-1 mRNA expression, transcription, and secretion. Inhibition of PI3K/Akt signaling blocked the binding of Smads 1/5 to the CSF-1 BMP-responsive element present in the CSF-1 promoter, resulting in attenuation of Smad-dependent CSF-1 transcription. Furthermore, PI3K inhibition and DN Akt prevented association of the transcriptional coactivator, CREB (cAMP response element binding protein) binding protein (CBP), with Smads 1/5. Together, these data for the first time demonstrate that PI3K-dependent Akt activation regulates BMP-2-induced CSF-1 expression and provides a mechanism for osteoblastic cell-assisted osteoclast differentiation.

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Macrophage colony-stimulating factor stimulates survival and chemotactic behavior in isolated osteoclasts.

Journal of Experimental Medicine ◽

10.1084/jem.178.5.1733 ◽

1993 ◽

Vol 178 (5) ◽

pp. 1733-1744 ◽

Cited By ~ 256

Author(s):

K Fuller ◽

J M Owens ◽

C J Jagger ◽

A Wilson ◽

R Moss ◽

...

Keyword(s):

Bone Resorption ◽

Osteoclast Formation ◽

Cell Polarization ◽

Colony Stimulating Factor ◽

Macrophage Colony Stimulating Factor ◽

Macrophage Colony ◽

And Migration ◽

Established Role ◽

Stimulating Factor

Macrophage colony-stimulating factor (M-CSF) is known to play an important role in osteoclast formation. However, its actions on mature cells have not been fully characterized. We now report that M-CSF dramatically stimulates osteoclastic motility and spreading; osteoclasts responded to a gradient of M-CSF with orientation, and random cell polarization occurred after isotropic exposure. M-CSF also supported the survival of osteoclasts by preventing apoptosis. Paradoxically, M-CSF inhibits bone resorption by isolated osteoclasts. We found that this was effected predominantly by reduction in the number of excavations. Thus, M-CSF showed a propensity to suppress resorption through a reduction in the proportion of cells that were resorbing bone. Our data suggest that apart from the established role of M-CSF in the provision of precursors for osteoclastic induction, a major role for M-CSF in bone resorption is to enhance osteoclastic survival, migration, and chemotaxis. It seems appropriate that during these processes resorptive functions should be suppressed. We suggest that M-CSF continues to modulate osteoclastic activity once osteoclasts are on resorptive sites, through regulation of the balance between resorption and migration, such that not only the quantity, but the spatial pattern of resorption can be controlled by adjacent M-CSF-secreting cells of osteoblastic lineage.

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