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HEMATOPOIESIS
From the Department of Cellular Pathology, St George's
Hospital Medical School, London, United Kingdom.
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.
(Blood. 2001;98:2707-2713) The osteoclast is the cell that resorbs bone.
Excessive activity by this cell is responsible for the development of
postmenopausal osteoporosis and for the destruction of bone that
accompanies inflammatory diseases such as rheumatoid arthritis.
Although it has been known for some time that the osteoclast derives
from the mononuclear phagocyte system and that it shares some
cell-surface markers with macrophages (see 1), it is also
distinctly different from any other known mononuclear phagocyte
derivative (see 2,3). Thus, osteoclasts lack many of the
antigens that are characteristic of macrophages, and they express high
levels of tartrate-resistant acid phosphatase (TRAP), vitronectin
receptors, and calcitonin receptors, which are absent from
macrophages.1-3 Most distinctively, osteoclasts ex vivo
excavate bone within hours, but macrophages show no excavation
whatsoever, even after extended incubation on bone
surfaces.4-6
It was recently found that osteoclastic differentiation is induced in
mononuclear phagocyte precursors by receptor activator of NF- The osteoclast derives from a bipotential, M-CSF-dependent precursor
shared with the macrophage. In the presence of RANKL and M-CSF, this
precursor differentiates into osteoclasts, but in M-CSF alone it
differentiates The role of M-CSF in osteoclast formation was established by the
discovery that M-CSF is absent in osteopetrotic (op/op)
mice,20,21 a mutant characterized by deficient bone
resorption caused by low numbers of osteoclasts. However, although
osteoclasts are reduced in number in these mutants, they are
nevertheless present, and most or all of the excess bone is eventually
resorbed.22 This suggests that other molecules can
substitute for the actions of M-CSF. In this context, controversial
data have been reported that granulocyte-macrophage CSF (GM-CSF)
can23 and cannot24 cure osteopetrosis in
op/op mice. In vitro, continuous incubation of murine hemopoietic
cells in GM-CSF strongly suppresses murine osteoclastic
differentiation,25-28 though GM-CSF does support the proliferation and survival of precursors that can form osteoclasts in
its absence.29,30 Recently, vascular endothelial growth factor (VEGF) was reported to support osteoclast formation in op/op
mice and in vitro, in the absence of exogenous M-CSF.31
Because M-CSF has several roles in osteoclast formation, we reasoned
that compensation might occur through a single factor or that each role
might be separately substituted by a different factor. We therefore
tested candidate factors, not only alone but also in combination, for
their ability to replace the need for M-CSF in osteoclast induction. We
were particularly interested in the ability of stem cell factor (SCF)
and Flt3 ligand (FL) to substitute for components of the action of
M-CSF, because these agents have actions on early precursors of the
mononuclear phagocyte lineage (see 32,33). In particular,
FL favors the induction of macrophagic versus other lineages and
supports the survival of immature mononuclear phagocytes. We found that
FL enabled the differentiation of functional osteoclasts by RANKL from
hemopoietic cells in the absence of M-CSF. Moreover, blockade of FL by
soluble receptors (Flt3-Fc) substantially reduced osteoclast
numbers in op/op mice. The mechanism by which FL partially
substituted for M-CSF appeared to be through supporting the
differentiation of adherent cells that express mRNA for RANK and
responsiveness to RANKL.
Mice
Media and reagents
Preparation of hemopoietic cells Bone marrow cells were isolated from MF1 mice as previously described.18 Mice were killed by cervical dislocation. Femora and tibiae were aseptically removed and dissected free of adherent soft tissue. The bone ends were cut, and the marrow cavity was flushed into a Petri dish by slowly injecting phosphate-buffered saline (PBS) at one end of the bone using a sterile 21-gauge needle. Bone marrow cells were carefully agitated through a 21-gauge needle to obtain a single cell suspension. Mononuclear cells were isolated by centrifugation of the bone marrow cell suspension on Histopaque (Sigma). The mononuclear cell fraction was resuspended in MEM-FBS, and incubated with cytokines as stated, at a density of 3 × 105 cells/mL in a 75-cm2 flask (Helena Biosciences, Sunderland, United Kingdom). After 6 to 24 hours, nonadherent cells were harvested, washed, and resuspended in MEM-FBS for further use.Hemopoietic cells were obtained from the spleens of op/op mice.34 Spleens were aseptically removed. The capsule was cut open, and spleen cells were squeezed from it into suspension. The suspension was disaggregated, and the mononuclear fraction was separated as above using Histopaque. Spleen cells were then washed, resuspended in MEM-FBS, and incubated with or without cytokines at 3 × 105 cells/mL in 75-cm2 flasks. After 6 to 24 hours, nonadherent cells were harvested, washed, and resuspended in MEM-FBS for further use. Osteoclast formation assay Nonadherent hemopoietic cells (3 × 104), prepared as above, were added to the wells of 96-well plates (Helena Biosciences) containing a 6-mm thermanox coverslip (Gibco BRL, Paisley, United Kingdom) or a slice of bovine cortical bone35 and incubated in a total volume of 200 µL MEM-FBS with cytokines and antibodies as stated. All cultures were fed every 2 to 3 days by replacing 100 µL culture medium with an equal volume of fresh medium and cytokines. Coverslips and bone slices were assessed for TRAP positivity or bone resorption, respectively, as described below.Assessment of TRAP expression and bone resorption by hemopoietic cells TRAP expression assessment and bone resorption by hemopoietic cells were performed as previously described.18,35 After aspiration of medium, cells on coverslips were washed in PBS, fixed in 10% formalin for 10 minutes, and stained for acid phosphatase in the presence of 0.05 M sodium tartrate. The substrate used was naphthol AS-BI phosphate.For bone resorption, bone slices were prepared as previously described.35 After incubation with hemopoietic cells, cells were removed from the surfaces of the bone slices to enable visualization of excavations. This was achieved by immersion of the bone slices in 10% (vol/vol) sodium hypochlorite (Lutterworth, Leicestershire, United Kingdom) for 10 minutes, followed by washing in water and dehydration in 70% ethanol. Bone slices were then mounted on stubs, sputter-coated with gold, and inspected in a Cambridge S90 scanning electron microscope (Cambridge Instruments, Cambridge, United Kingdom). Reverse-transcription-polymerase chain reaction analysis Bone marrow or spleen cells prepared as above were washed, resuspended, and incubated at 2 × 105/mL in 6-well plates (Helena Biosciences) with or without the stated cytokines for 3 days. Wells were then washed twice to remove nonadherent cells. RNA was extracted using an RNeasy mini kit (Qiagen, Crawley, United Kingdom) according to the manufacturer's instructions. Total RNA was reverse transcribed using MMLV (Gibco) using random hexamers (100 pmol) (Pharmacia, St Albans, United Kingdom) according to manufacturer's instructions. Polymerase chain reaction (PCR) primers were as follows: actin, 5'-GTTACCAACTGGCACGATATGG-3' (forward) and 5'-GATCTTGATCTTCATGGTGC-3' (reverse); RANK, 5'GAGGCATTATGAGCATCTCGG-3' (forward) and 5'-TTTCTTTTGTCAGGTGCTTTTCAG-3' (reverse).cDNAs were amplified for 25 to 38 cycles using Platinum Taq (2.5 U) (Gibco), 0.2 mM of each dNTP, 1.5 mM MgCl2, and 0.2 µM each primer. Each cycle consisted of 45-second denaturation at 94°C, 45-second denaturation at 60°C, and 60-second denaturation at 72°C. Product was measured during the exponential phase and checked for size by Southern blot analysis using internal oligos (actin, 481-531 nt; RANK, 721-770 nt). Effect of Flt3 ligand on osteoclasts isolated from rat bone Osteoclasts were isolated from 2-day-old rats as previously described.35 Briefly, femora were removed from 2-day-old Wistar rats, cleaned of adherent soft tissue, and curetted with a scalpel into medium 199 (Imperial). Curetting was agitated with a Pasteur pipette. Larger fragments were allowed to sediment for 30 seconds, and the resultant suspension was sedimented onto plastic coverslips or bone slices for 20 minutes. Substrates were washed vigorously to remove nonadherent cells and were incubated for 2 hours or 24 hours in MEM with 1 ng/mL bovine serum albumin with cytokines as described above. Coverslips and bone slices were then processed for assessment of TRAP positivity or bone resorption, respectively, as described above.Effect of Flt3-Fc in vivo Op/op mice were administered subcutaneous injections of Flt3-Fc (5 µg) or vehicle on each of 3 days. Two mice were given vehicle on each of the 3 days. Three mice were given Flt3-Fc on the first day, 2 were given it on the second, and 1 of these 2 was injected on the third day. Mice were killed 24 hours after the last injection. Femurs were removed and fixed in 10% formalin for 24 hours and were decalcified in 10% EDTA (pH 7.0) for 7 days. Decalcified bones were embedded in paraffin, and sections were cut and processed for histochemical localization of TRAP by a modification of the method of Burstone.36 The number of TRAP-positive cells lining bone surfaces was assessed by a modification of the method previously described.37 Data for bone perimeter and TRAP-positive cells were input into a computer and analyzed using histomorphometry software (Osteomeasure, Osteometrics, Atlanta, GA). The portion of bone between epiphyseal plates was selected for examination. The number of TRAP-positive cells per centimeter endosteal surface was counted "blind" in the diaphysis and metaphysis. TRAP-positive mononuclear cells were discriminated from TRAP-positive multinuclear (including binuclear) cells and then counted.Statistics The significance of differences between means was evaluated by the Student t test. Linear regression analysis with number of injections versus TRAP-positive cells was performed using Statview 5.0 (Abacus, Berkeley, CA). P < .05 was considered significant.
We initially tested the ability of agents known to be able to
support some or all stages of development of the mononuclear phagocytic
lineage to replace M-CSF in osteoclast-induction by RANKL. To do this,
these factors, alone or in combination, were substituted for M-CSF in
an assay in which osteoclast formation is dependent on exogenous M-CSF.
In this assay, bone marrow cells are depleted of stromal cells by
incubation for 24 hours in M-CSF, followed by incubation of the
nonadherent bone marrow cells for 6 days in M-CSF with RANKL. M-CSF is
present in both phases to support precursors. Thus, to test the ability
of cytokines to compensate for the M-CSF deficiency, the candidates
replaced M-CSF in both preincubation and osteoclast-inductive phases.
We found that all cultures containing FL developed strongly
TRAP-positive cells (Table 1). GM-CSF,
interleukin-3, and SCF were unable to support the differentiation of
TRAP-positive cells by RANKL. VEGF alone (with RANKL) did not induce
TRAP-positive cells (data not shown) and did not synergize with FL
(Table 1).
Two distinct populations of cells were present: TRAP-negative
macrophagelike cells and strongly TRAP-positive cells (Figure 1). The absolute number of TRAP-positive
cells that formed when bone marrow cells were incubated with FL was
small but similar, as a proportion of total cells present, to that
observed in the presence of M-CSF (Figure 1). This is consistent with a
model in which FL shares with M-CSF the capacity to support
osteoclastic differentiation, but it lacks its proliferative action so
that both in vitro and in vivo the total number of osteoclastic cells formed was small.
Although FL induced cells that were strongly TRAP positive (Figure 1), they were almost all mononuclear. However, the cells made excavations when they were incubated on bone slices (Figure 1). Most of the osteoclasts in op/op mice are mononuclear.23 This propensity for mononuclearity in vivo and in vitro may reflect an inability of FL to compensate for M-CSF in the induction of fusion. An alternative explanation is that fusion, which requires cells to make contact, is less common at the low cell densities achieved without M-CSF. It has been noted that, especially at low densities in vitro, some osteoclastic cells remain mononuclear but are nevertheless capable of bone resorption.38-40 Like M-CSF, FL showed a capacity to support the expression of mRNA for
RANK in the adherent cells that develop from nonadherent bone marrow
cells in culture (Figure 2A). No RANK
mRNA was detected in cultures incubated with VEGF (100 ng/mL) or IL-3
(1 ng/mL) (data not shown). To determine whether TRAP-positive cell
differentiation and RANK expression in the cultures of cells from
normal mice was attributable to FL alone or whether it represented
synergy with endogenous M-CSF, the experiments were repeated using
hemopoietic cells from op/op mice, which do not express M-CSF. As
observed using cells from normal mice, mRNA for RANK was detected only after incubation in M-CSF or FL (Figure 2B). In addition, similar to
cultures of cells from normal mice, FL supported the differentiation of
TRAP-positive cells indistinguishable from those seen in normal animals
in a dose-dependent manner (Figure 3).
The total number of cells induced by FL was greater from op/op
hemopoietic cells than from wild-type cells. Although the populations
of cells from spleen (op/op) and marrow (wild-type) are not readily
comparable, a similar 3-fold increase in M-CSF-derived colonies was
noted in op/op spleen versus wild-type bone marrow, possibly reflecting an attempted hemopoietic compensation for the deficiency of mature cells.41 TRAP-positive cell formation was not inhibited by
neutralizing antibody to GM-CSF. However, proliferation was inhibited,
suggesting that GM-CSF is present in these cultures. GM-CSF has complex
effects on osteoclast precursors
M-CSF supports not only osteoclastic differentiation but also the
survival of mature osteoclasts.13,42 Therefore, we tested the effects of FL on osteoclasts isolated from neonatal rat long bones.
FL showed no significant effect on the survival of isolated osteoclasts
(Figure 4) and did not influence the
number or plan area of bone surface resorbed by these cells
(data not shown).
A critical prediction of the notion that FL compensates for lack of
M-CSF in op/op mice is that blockade of FL signaling in these mice
should reduce osteoclast number. To blockade FL signaling, op/op mice
were injected with 5 µg soluble receptor for FL (Flt3-Fc) or vehicle
daily for up to 3 days. We found (Figure
5) a highly significant inverse
correlation between the number of daily injections of Flt3-Fc and the
number of osteoclasts per centimeter of bone surface
(P < .02) or per section (P = .003). We also
confirmed that many osteoclasts in op/op mice showed only one nucleus,
and we found that the proportion of such osteoclasts was increased by
soluble receptor (Figure 5). This suggests that the reduction in
osteoclast number understates the reduction in osteoclast cell bulk brought about by blockade of FL.
Osteoclast formation and bone resorption occur, albeit at reduced levels, in the op/op mouse, which lacks any M-CSF.20-22 This suggests that factors exist in vivo that can partially compensate for M-CSF deficiency. We tested several putative or potential M-CSF surrogates, including SCF, FL, VEGF, GM-CSF, and IL-3, for their ability to substitute for M-CSF in osteoclast formation. Only FL was able to support RANKL-induced differentiation of TRAP-positive cells from hemopoietic cells. Such cells were also formed from the hemopoietic cells of op/op mice. Although only small numbers of TRAP-positive cells formed in the presence of FL, the proportion of adherent cells that were TRAP positive was similar to the proportion seen after incubation in M-CSF. This pattern suggests that FL can replace M-CSF for RANKL responsiveness but not for proliferation, and it is consistent with both the presence and the scarcity of osteoclasts in op/op mice. Also consistent with this role for FL, we found that the injection of soluble decoy receptors for FL into op/op mice dramatically reduced osteoclast number, suggesting that FL compensates in vivo for the absence of M-CSF. There have been no previous reports of osteoclastic differentiation in vitro in the absence of M-CSF. It has been reported that GM-CSF can23 and cannot24 increase bone resorption in op/op mice. In vitro, GM-CSF strongly inhibits osteoclast formation from murine hemopoietic cells,25-28 and GM-CSF is unable to support osteoclast formation in cultures of op/op cells.34 However, GM-CSF can support osteoclast formation in vitro if precursors are incubated in GM-CSF and then transferred to RANKL/M-CSF-expressing cultures of stromal cells.29 Thus, if osteoclast formation is enhanced by GM-CSF in op/op mice, this is likely to occur through an increase by GM-CSF in the provision of hemopoietic precursors available for osteoclast-induction by RANKL/FL. Recently, it was shown that GM-CSF induces the expression of RANK in precursors, but then, in the presence of RANKL, it induces dendritic cell rather than osteoclastic differentiation.43 Hence, it appears that GM-CSF and M-CSF direct differentiation induction by RANKL into the alternative destinies of dendritic cells and osteoclasts, respectively. This makes it unlikely that GM-CSF compensates directly for M-CSF deficiency in op/op mice. It has also been suggested that VEGF compensates for the lack of M-CSF in vivo and in vitro.31 However, we found that VEGF did not induce osteoclastic differentiation or mRNA for RANK. This makes it unlikely that VEGF substitutes directly for M-CSF. In fact, the experiments31 reporting osteoclast induction by VEGF in vitro used not op/op but wild-type bone marrow cells and, moreover, did not include VEGF-free control cultures. Thus, the induction of osteoclastic differentiation by M-CSF produced by contaminating stromal cells or macrophages was not excluded and indeed was especially likely to have occurred because VEGF supports bone marrow endothelial stromal cells, which express M-CSF and FL.44 In vivo, bone resorption has been shown to be dependent on VEGF-mediated angiogenesis,45 and this dependency might account for the inhibition of bone resorption by the blockade of VEGF in vivo in those31 experiments. Alternatively, because enhancement of the survival of hematogenous osteoclastic precursors augments bone resorption in op/op mice,46 VEGF blockade might impair osteoclast function in op/op mice by interfering with endothelial cell-mediated transit of hematogenous precursors to bone surfaces. Flt3 is widely expressed by hemopoietic cells and, consistent with our observation that FL enables TRAP cell induction, is expressed by hemopoietic cells known to be precursors of osteoclasts.32,33,47,48 Its ligand, FL, is widely expressed in bone and many other tissues and exerts effects on hemopoietic cells in synergy with other cytokines (see 32,33,48). FL shares several characteristics with SCF, but though SCF favors the differentiation of granulocytes, eosinophils, and red blood cells, FL enhances the production of mononuclear phagocytes, including likely precursors of osteoclasts and dendritic cells.32,33,48 The ability of FL but not SCF to restore RANKL responsiveness in vitro suggests that osteoclasts are part of the spectrum of differentiation in hemopoietic cells facilitated by FL. Recently, it was shown that nonadherent hemopoietic precursors do not express RANK in the absence of M-CSF and that RANK is induced simultaneously with adhesion receptors.19 Therefore, because our cultures were derived from nonadherent cells, our results suggest that FL similarly induces the expression of mRNA for RANK and RANKL responsiveness in such RANK-negative nonadherent cells. This is strongly supported by the similar results using spleen cells from op/op animals in which endogenous M-CSF cannot be responsible for the induction of mRNA for RANK. Thus, FL might substitute for M-CSF in op/op mice primarily through the induction of responsiveness to RANKL. We found that although FL facilitated osteoclast formation, it had no effect on the survival or function of mature cells in vitro. This pattern of decreasing responsiveness to FL with maturation is also observed in other lineages. However, osteoclast numbers were reduced rapidly in vivo by soluble Flt3. We found that FL does not augment the survival of existing osteoclasts; presumably FL blockade reduces the supply of replacement osteoclasts. This mechanism is also consistent with the greater proportion of mononuclear cells in Flt3-Fc-treated mice: if osteoclasts are scarce, there are fewer opportunities for fusion. It is possible that FL participates in the maintenance of osteoclastic precursors on bone surfaces in normal animals. Recent evidence suggests that although osteoclasts have their origin in hematogenous cells and can be supplied from the circulation during development or in conditions of physiological stress, they derive under physiological conditions from a self-sustaining precursor that becomes established on the bone surface49 (and see 50). If this is so, FL might be more suited to the long-term support of such cells than is M-CSF: precursors rapidly become refractory to osteoclast induction in M-CSF,16-19 whereas FL can maintain the responsiveness of precursors to cytokines.51 Because the circulation can supply osteoclast precursors, such a role is unlikely to be essential (a nonessential role is also consistent with the lack of reports of an osteopetrotic phenotype in mice deleted of the gene for FL).52,53 Nevertheless, local osteoclast precursors might facilitate rapid resorptive responses. The role of FL in the physiology of normal bone is being addressed. We found that the blockade of FL signaling by the administration of Flt3-Fc dramatically reduced the number of osteoclasts in the bones of op/op mice. This suggests that FL accounts for the presence of osteoclasts in these mice, despite the absence of M-CSF. Although we have not tested the ability of FL to also increase osteoclast formation in vivo, this result is anticipated from experiments in which it was shown that the systemic administration of FL increases the number of osteoclast precursors,48 consistent with our in vivo and in vitro observations. Our results also suggest that, in addition to providing precursors, FL induces the expression of RANK in osteoclast precursors. It has been shown that osteopetrosis in op/op mice resolves with age. Although FL appears to partially compensate for the absence of M-CSF in these mice and might explain the presence of osteoclasts, we do not know whether this is related to the spontaneous resolution of osteopetrosis that occurs in these mice later in life. As growth rate slows with age, the rate of bone formation decreases and with it the resorptive burden, so that spontaneous cure might reflect the ability of suboptimal osteoclast function to catch up when formation rates decline. Alternatively, the ability of FL to support osteoclast precursors might be enhanced once these become established on bone surfaces, as discussed above; or spontaneous cure might occur through an age-related increase in expression of FL or through the expression of other, as-yet-unidentified compensatory agents. Injection of FL has been shown to increase dendritic cell numbers in
vivo.54 Because RANKL can induce dendritic cell
differentiation in vitro,43 our observation that FL
induces RANKL responsiveness provides a mechanism for osteoclast
induction and dendritic cell induction by FL. Indeed, the induction of
RANKL responsiveness may reflect a more general mechanism by which FL
favors the differentiation of certain hemopoietic lineages
Submitted April 19, 2001; accepted June 25, 2001.
Supported by The Wellcome Trust.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: T. J. Chambers, Department of Cellular Pathology, St George's Hospital Medical School, Cranmer Terrace, London, United Kingdom; e-mail: t.chambers{at}sghms.ac.uk.
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© 2001 by The American Society of Hematology.
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  S. D. Yogesha, S. M. Khapli, R. K. Srivastava, L. S. Mangashetti, S. T. Pote, G. C. Mishra, and M. R. Wani IL-3 Inhibits TNF-{alpha}-Induced Bone Resorption and Prevents Inflammatory Arthritis J. Immunol., January 1, 2009; 182(1): 361 - 370. [Abstract] [Full Text] [PDF]
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K. P. A. MacDonald, V. Rowe, H. M. Bofinger, R. Thomas, T. Sasmono, D. A. Hume, and G. R. Hill The Colony-Stimulating Factor 1 Receptor Is Expressed on Dendritic Cells during Differentiation and Regulates Their Expansion J. Immunol., August 1, 2005; 175(3): 1399 - 1405. [Abstract] [Full Text] [PDF]
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 D. A. Hume, I. L. Ross, S. R. Himes, R. T. Sasmono, C. A. Wells, and T. Ravasi The mononuclear phagocyte system revisited J. Leukoc. Biol., October 1, 2002; 72(4): 621 - 627. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
B
ligand RANKL (also known as TRANCE, ODF, OPGL, and TNFSF11), which was
originally identified as a T cell-derived product that stimulates
dendritic cells.
with increasing resistance to osteoclast-induction
