Roles of macrophage-colony stimulating factor and osteoclast differentiation factor in osteoclastogenesis

2000 ◽  
Vol 18 (4) ◽  
pp. 177-184 ◽  
Author(s):  
Taro Tsurukai ◽  
Nobuyuki Udagawa ◽  
Kenichiro Matsuzaki ◽  
Naoyuki Takahashi ◽  
Tatsuo Suda
Keyword(s):  
Osteoclast Differentiation ◽  
Colony Stimulating Factor ◽  
Differentiation Factor ◽  
Osteoclast Differentiation Factor ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

scholarly journals A Combination of Osteoclast Differentiation Factor and Macrophage-Colony Stimulating Factor Is Sufficient for both Human and Mouse Osteoclast Formation in Vitro

Endocrinology ◽  
1998 ◽  
Vol 139 (10) ◽  
pp. 4424-4427 ◽  
Author(s):  
Julian M. W. Quinn ◽  
Jan Elliott ◽  
Matthew T. Gillespie ◽  
T. John Martin
Keyword(s):  
Bone Resorption ◽  
Stromal Cells ◽  
Osteoclast Differentiation ◽  
Colony Stimulating Factor ◽  
Human Osteoclast ◽  
Osteoclast Differentiation Factor ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Abstract Both human and murine osteoclasts can be derived in vitro from hematopoietic cells or monocytes that are cocultured with osteoblasts or marrow-derived stromal cells. The osteoclastogenic stimulus provided by murine osteoblasts and marrow-derived stromal cells is now known to be mediated by osteoclast differentiation factor (ODF), a membrane-bound tumor necrosis factor-related ligand. This study demonstrates that mouse spleen cells and monocytes form osteoclasts when cultured in the presence of macrophage-colony stimulating factor (M-CSF) and a soluble form of murine ODF (sODF). Numerous multinucleated osteoclasts expressing tartrate resistant acid phosphatase (TRAP) and calcitonin receptor (CTR) formed within 7 days of culture and engaged in extensive lacunar bone resorption. Osteoclast number and bone resorption area was dependent on sODF concentration. Long-term cultured human monocytes also formed bone resorbing osteoclasts in response to co-stimulation by sODF and M-CSF, although this required more than 11 days in culture. This human osteoclast differentiation was strongly inhibited by granulocyte-macrophage colony stimulating factor. This study further characterises murine osteoclast differentiation caused by sODF and M-CSF co-stimulation in vitro, and shows that the same co-stimulation causes human osteoclast differentiation to occur. We propose that this methodology can be employed to investigate the direct effects of cytokines and other factors on human osteoclast differentiation.

Local concentrations of macrophage colony-stimulating factor mediate osteoclastic differentiation

1995 ◽  
Vol 269 (6) ◽  
pp. E1024-E1030 ◽  
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.

FLT3 ligand can substitute for macrophage colony-stimulating factor in support of osteoclast differentiation and function

Blood ◽  
2001 ◽  
Vol 98 (9) ◽  
pp. 2707-2713 ◽  
Author(s):  
Jeny Maree Lean ◽  
Karen Fuller ◽  
Timothy John Chambers
Keyword(s):  
Bone Marrow ◽  
Bone Resorption ◽  
Bone Marrow Cells ◽  
Osteoclast Differentiation ◽  
Colony Stimulating Factor ◽  
Flt3 Ligand ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor ◽  
Marrow Cells

Abstract Although bone resorption and osteoclast numbers are reduced in osteopetrotic (op/op) mice, osteoclasts are nevertheless present and functional, despite the absence of macrophage colony-stimulating factor (M-CSF). This suggests that alternative factors can partly compensate for the crucial actions of M-CSF in osteoclast induction. It was found that when nonadherent bone marrow cells were incubated in RANKL with Flt3 ligand (FL) without exogenous M-CSF, tartrate-resistance acid phosphatase (TRAP)–positive cells were formed, and bone resorption occurred. Without FL, only macrophagelike TRAP-negative cells were present. Granulocyte-macrophage CSF, stem cell factor, interleukin-3, and vascular endothelial growth factor could not similarly replace the need for M-CSF. TRAP-positive cell induction in FL was not due to synergy with M-CSF produced by the bone marrow cells themselves because FL also enabled their formation from the hemopoietic cells of op/op mice, which lack any M-CSF. FL appeared to substitute for M-CSF by supporting the differentiation of adherent cells that express mRNA for RANK and responsiveness to RANKL. To determine whether FL can account for the compensation for M-CSF deficiency that occurs in vivo, FL signaling was blockaded in op/op mice by the injection of soluble recombinant Flt3. It was found that the soluble receptor induced a substantial decrease in osteoclast number, strongly suggesting that FL is responsible for the partial compensation for M-CSF deficiency that occurs in these mice.

Engineering a monomeric variant of macrophage colony-stimulating factor (M-CSF) that antagonizes the c-FMS receptor

2017 ◽  
Vol 474 (15) ◽  
pp. 2601-2617 ◽  
Author(s):  
Yuval Zur ◽  
Lior Rosenfeld ◽  
Anna Bakhman ◽  
Stefan Ilic ◽  
Hezi Hayun ◽  
...  
Keyword(s):  
Bone Metastasis ◽  
Tyrosine Kinase ◽  
Osteoclast Differentiation ◽  
Bone Diseases ◽  
Tyrosine Kinase Receptor ◽  
Colony Stimulating Factor ◽  
Starting Point ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Enhanced activation of the signaling pathways that mediate the differentiation of mononuclear monocytes into osteoclasts is an underlying cause of several bone diseases and bone metastasis. In particular, dysregulation and overexpression of macrophage colony-stimulating factor (M-CSF) and its c-FMS tyrosine kinase receptor, proteins that are essential for osteoclast differentiation, are known to promote bone metastasis and osteoporosis, making both the ligand and its receptor attractive targets for therapeutic intervention. With this aim in mind, our starting point was the previously held concept that the potential of the M-CSFC31S mutant as a therapeutic is derived from its inability to dimerize and hence to act as an agonist. The current study showed, however, that dimerization is not abolished in M-CSFC31S and that the protein retains agonistic activity toward osteoclasts. To design an M-CSF mutant with diminished dimerization capabilities, we solved the crystal structure of the M-CSFC31S dimer complex and used structure-based energy calculations to identify the residues responsible for its dimeric form. We then used that analysis to develop M-CSFC31S,M27R, a ligand-based, high-affinity antagonist for c-FMS that retained its binding ability but prevented the ligand dimerization that leads to receptor dimerization and activation. The monomeric properties of M-CSFC31S,M27R were validated using dynamic light scattering and small-angle X-ray scattering analyses. It was shown that this mutant is a functional inhibitor of M-CSF-dependent c-FMS activation and osteoclast differentiation in vitro. Our study, therefore, provided insights into the sequence–structure–function relationships of the M-CSF/c-FMS interaction and of ligand/receptor tyrosine kinase interactions in general.

Mechanical strain inhibits expression of osteoclast differentiation factor by murine stromal cells

2000 ◽  
Vol 278 (6) ◽  
pp. C1126-C1132 ◽  
Author(s):  
Janet Rubin ◽  
Tamara Murphy ◽  
Mark S. Nanes ◽  
Xian Fan
Keyword(s):  
Stromal Cells ◽  
Mechanical Strain ◽  
Osteoclast Differentiation ◽  
Osteoclast Formation ◽  
Thymidine Uptake ◽  
Differentiation Factor ◽  
Osteoclast Differentiation Factor ◽  
Membrane Bound ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony

Normal dynamic loading prevents bone resorption; however, the means whereby biophysical factors reduce osteoclast activity are not understood. We show here that mechanical strain (2% at 10 cycles per minute) applied to murine marrow cultures reduced 1,25(OH)2D3-stimulated osteoclast formation by 50%. This was preceded by decreased expression of osteoclast differentiation factor (ODF/TRANCE). RT-PCR for ODF/TRANCE revealed that ODF/TRANCE mRNA in strained cultures was 59 ± 3% of that seen in control cultures. No significant effects on total cell count, thymidine uptake, or alkaline phosphatase activity were induced by strain. To isolate the cell targeted by strain, primary stromal cells were cultured from marrow. Mechanical strain also reduced mRNA for ODF/TRANCE to 60% that of control in these cells. In contrast, mRNA for membrane-bound macrophage colony-stimulating factor was not significantly affected. Soluble ODF (∼2 ng/ml) was able to reverse the effect of strain, returning osteoclast numbers to control. Because osteoclast formation is dependent upon ODF/TRANCE expression, strain-induced reductions in this factor may contribute to the accompanying reduction in osteoclastogenesis.

Bifurcation of osteoclasts and dendritic cells from common progenitors

Blood ◽  
2001 ◽  
Vol 98 (8) ◽  
pp. 2544-2554 ◽  
Author(s):  
Takeshi Miyamoto ◽  
Osamu Ohneda ◽  
Fumio Arai ◽  
Katsuya Iwamoto ◽  
Seiji Okada ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Early Stage ◽  
Osteoclast Differentiation ◽  
Precursor Cells ◽  
Lineage Commitment ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Abstract Osteoclasts and dendritic cells are derived from monocyte/macrophage precursor cells; however, how their lineage commitment is regulated is unknown. This study investigated the differentiation pathways of osteoclasts and dendritic cells from common precursor cells at the single-cell level. Osteoclastogenesis induced by macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor–κB ligand (RANKL) or tumor necrosis factor-α (TNF-α) is completely inhibited by addition of granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-3 at early stages of differentiation. GM-CSF–treated cells express both c-Fms and RANK and also low levels of CD11c and DEC205, which are detected on dendritic cells. Addition of GM-CSF also reduces expression of both c-Fos and Fra-1, which is an important event for inhibition of osteoclastogenesis. Overexpression of c-Fos by retroviral infection or induction in transgenic mice can rescue a failure in osteoclast differentiation even in the presence of GM-CSF. By contrast, differentiation into dendritic cells is inhibited by M-CSF, indicating that M-CSF and GM-CSF reciprocally regulate the differentiation of both lineages. Dendritic cell maturation is also inhibited when c-Fos is expressed at an early stage of differentiation. Taken together, these findings suggest that c-Fos is a key mediator of the lineage commitment between osteoclasts and dendritic cells. The lineage determination of osteoclast progenitors seen following GM-CSF treatment functions through the regulation of c-Fos expression.

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