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Direct Macrophage Activation by TNF-
to Osteoclastic or Cytocidal Phenotype1
Department of Experimental Pathology, St. George’s Hospital Medical School, London, United Kingdom
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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B ligand (RANKL), osteoclast
differentiation factor (ODF), osteoprotegerin ligand (OPGL), and
TNFSF11) induces the differentiation of progenitors of the mononuclear
phagocyte lineage into osteoclasts in the presence of M-CSF.
Surprisingly, in view of its potent ability to induce inflammation and
activate macrophage cytocidal function, TNF-
has also been found to
induce osteoclast-like cells in vitro under similar conditions. This
raises questions concerning both the nature of osteoclasts and the
mechanism of lineage choice in mononuclear phagocytes. We found that,
as with TRANCE, the macrophage deactivator TGF-ß1
strongly promoted TNF--induced osteoclast-like cell formation from
immature bone marrow macrophages. This was abolished by IFN-
.
However, TRANCE did not share the ability of TNF- to activate NO
production or heighten respiratory burst potential by macrophages, or
induce inflammation on s.c. injection into mice. This suggests that
TGF-ß1 promotes osteoclast formation not only by
inhibiting cytocidal behavior, but also by actively directing TNF-
activation of precursors toward osteoclasts. The osteoclast appears to
be an equivalent, alternative destiny for precursors to that of
cytocidal macrophage, and may represent an activated variant of
scavenger macrophage. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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vß3), and express
calcitonin receptors that are absent from macrophages
(1, 2, 3). Most distinctively, osteoclasts ex vivo excavate
bone within hours, but macrophages show no excavation whatsoever, even
on extended incubation on bone surfaces (4, 5, 6).
It was recently found that osteoclast differentiation is induced in
mononuclear phagocyte precursors by TNF-related activation-induced
cytokine (TRANCE; also called receptor activator of NF-B ligand
(RANKL), osteoclast differentiation factor (ODF), osteoprotegerin
ligand (OPGL), and TNFSF11), which was originally identified as a
member of the TNF superfamily that stimulates dendritic cells
(7, 8, 9). TRANCE is expressed by osteoblastic and bone
marrow stromal cells, and soluble recombinant TRANCE, with M-CSF,
substitutes for stromal cells in osteoclast formation and
activation (10, 11, 12, 13). Transgenic experiments have shown
that deletion of the gene for TRANCE, or overexpression of OPG, a
soluble decoy receptor for TRANCE, is associated with failure of
osteoclast formation and osteopetrosis (14, 15, 16).
Recently, TNF- was reported also to be able to induce osteoclastic
cells from bone marrow macrophages in vitro (17). This was
unexpected because TNF- plays a major role in host defense. It
exerts proinflammatory activities through a range of cell types,
including mononuclear phagocytes, in which it is responsible for the
activation of bacteriocidal/cytocidal systems (see Refs. 18, 19). The specialized function of the osteoclast seems quite
distinct from that of such macrophages, yet TNF- can activate both
phenotypes from the same precursors.
The observation raises two major questions. First, if TNF- is
capable of activation of macrophages both to cytocidal and osteoclastic
phenotypes, does TRANCE share this capacity? The number and diversity
of cells and tissues that express TRANCE (20) implies
actions beyond those already described in bone and lymphoid biology.
TRANCE might be a stromal cell counterpart of the predominantly
macrophage-derived TNF-, as a mediator of host defense. Therefore,
we tested the ability of TRANCE to activate macrophages for NO
production in vitro and to exert proinflammatory TNF--like activity
in vivo.
The second question posed by the ability of TNF- to induce
osteoclastic cells in vitro is: Why are these cells not a common
feature of inflamed tissues? It seems most likely that additional
signals are present in vivo that are important in determining the
direction of macrophagic activation. For example, although IFN-
primes macrophages for cytocidal activation by TNF-, it has been
suggested that TGF-ß1 deactivates macrophages
in the subsequent healing phase (21, 22, 23 ; see Refs.
24, 25 for reviews). We found that
TGF-ß1 substantially increased the proportion
of precursors that formed osteoclastic cells in culture in response to
TNF-. This suggests a model in which the osteoclast is an
alternative and equivalent destiny for precursors to that of the
cytocidal macrophage.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Cells were incubated in MEM with Earle’s salts supplemented
with 10% FBS, 2 mM glutamine, 100 IU/ml benzylpenicillin, and 100
µg/ml streptomycin (all from Imperial Laboratories, Andover, Hants,
U.K.). Recombinant human M-CSF was provided by Genetics Institute
(Cambridge, MA); soluble recombinant human TRANCE was obtained from
Insight Biotechnology (Wembley, Middlesex, U.K.); and purified human
TGFß1, recombinant murine IFN- and TNF-,
and pan-specific TGF-ß-neutralizing Ab were purchased from R&D
Systems (Abingdon, Oxon, U.K.). All other reagents were obtained from
Sigma (Poole, Dorset, U.K.) unless otherwise stated. All incubations
were performed at 37°C in a humidified atmosphere of 5%
CO2 in air.
Isolation and culture of bone marrow precursors
Bone marrow cells were isolated from 5- to 8-wk-old MF1 mice as described previously (26). 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 out into a petri dish by slowly injecting medium 199 (Imperial) at one end of the bone using a sterile 21-gauge needle. The bone marrow suspension was carefully agitated with a plastic Pasteur pipette to obtain a single-cell suspension. The bone marrow cells were washed twice, resuspended in MEM containing 10% FBS, and incubated for 24 h in M-CSF (5 ng/ml) at a density of 3 x 105 cells/ml in a 75-cm2 flask (Helena Biosciences, Sunderland, Tyne & Weir, U.K.). After 24 h, nonadherent cells were harvested, washed, and resuspended (3 x 105/ml) in MEM-FBS. This suspension was added (100 µl/well) to the wells of 96-well plates (Helena Biosciences) containing a 6-mm Thermanox coverslip (Life Technologies, Paisley, U.K.). To each of these wells an additional 100 µl of medium containing M-CSF (60 ng/ml) with/without cytokines was added. Cultures were fed every 2–3 days by replacing 100 µl of culture medium with an equal quantity of fresh medium and reagents. Absence of contaminating stromal cells was confirmed in cultures in which M-CSF was omitted. Such cultures showed no cell growth. Cultures were assessed for TRAP or NO production as described below.
Isolation and culture of resident peritoneal macrophages
MF1 mice (5–8 wk old) were anesthetized and exsanguinated. Three milliliters of Dulbecco’s PBS was injected i.p., agitated, and removed. The suspension was centrifuged at 1200 x g at 4°C for 10 min. Cells were resuspended (106/ml) in MEM-FBS and plated at 105/well in 96-well plates. After incubation for 30 min, cultures were washed and cultured as described for bone marrow cells.
TRAP cytochemistry
Osteoclast formation was evaluated by quantification of TRAP-positive cell number using a modification of the method of Burstone (27). After incubation, coverslips or bone slices were washed in PBS, fixed in 10% Formalin for 10 min, and stained for acid phosphatase in the presence of 0.05 M sodium tartrate (Sigma). The substrate used was naphthol AS-BI phosphate (Sigma). The preparations were then counterstained (hematoxylin), and cells were counted using an eyepiece graticule.
Quantification of NO2- release
The accumulation of NO2- in the culture supernatants of bone marrow cells was quantified in 96-well plates using the Greiss reagent (Promega, Madison, WI) as described by Ding et al. (28). Fifty-microliter aliquots of the culture supernatants were dispensed into 96-well plates and mixed with 50 µl of 1% (w/v) sulfanilamide, incubated for 10 min at room temperature, before adding 50 µl of 0.1% (w/v) naphthyl-ethylenediamine hydrochloride and 2.5% (v/v) concentrated H3PO4. A standard curve consisting of 0.1–5.0 nmol of Na NO2/100 µl was prepared in culture medium. After incubation at ambient room temperature for 10 min, absorbance was quantified at 550 nM in a micro-ELISA reader (Titertek Multiscan Plus; Life Sciences, Basingstoke, Hampshire, U.K.). Concentrations of NO2- were interpolated from the NaNO2 standard curve.
Quantification of respiratory burst
The respiratory burst of adherent bone marrow-derived cells was
assessed by the stimulus-induced reduction of cytochrome c.
Bone marrow cells were isolated and incubated as above for 3 days in
24-well plates (Helena Biosciences) (6 x
105 cells/ml) in M-CSF (30 ng/ml) with or without
TNF- (100 ng/ml) or TRANCE (100 ng/ml). Culture medium was then
removed and replaced with 1 ml of Krebs-Ringer phosphate buffer (121 mM
NaCl, 5 mM KCl, 1.3 mM CaCl2, 1.2 mM
MgSO4, 3.1 mM NaH2
PO4, 12.5 mM
Na2HPO4, and 11 mM
dextrose, pH 7.3) containing 80 µM ferricytochrome c and
10-6 M PMA. The cells were incubated for 90 min
at 37°C, the supernatants were collected, and the absorbance was read
at 550 nm. The amount of cytochrome c reduced was calculated
by using a differential molar extinction coefficient of 2.1 x
104 M-1
cm-1 (29), and results were
expressed as nanomoles of O2-
produced per 106 cells. Cultures were fixed in
Formalin after incubation, and cells were counted using an eyepiece
graticule. Cultures were set up in triplicate.
Mouse footpad injections
Assessment of the ability of TNF- and TRANCE to induce
inflammation was performed as described by Sharpe et al.
(30). Then, 0.05 ml of PBS containing 0.1% BSA and either
50–100 ng of TNF-, or TNF- heat treated (90°C for 1 h),
or TRANCE (50–500 ng) was injected s.c. into the left hind footpad of
5- to 8-wk-old MF1 mice. An identical amount of diluent, not containing
the test substance, was injected into the right hind footpad. At time
intervals (6–48 h), animals were killed and footpad tissue was
prepared for light microscopy. For this, tissue was fixed in 10%
buffered Formalin for 24 h and routinely processed.
Paraffin-embedded tissue sections were stained with hematoxylin and
eosin. The sections were examined "blind" for inflammatory
cells.
Statistical analysis
Differences between groups were analyzed with the unpaired Student’s t test using StatView (Abacus Concepts, Berkeley, CA). p < 0.05 was considered to be significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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was
added to M-CSF-dependent precursors that had been incubated in M-CSF
for 3 days (bone marrow macrophages), there was a dose-dependent
production of strongly TRAP-positive cells (Fig. 1
). The proportion of bone marrow
macrophages that became TRAP-positive was quite small (see Fig. 1). As
previously noted (17), the majority of these TRAP-positive
cells were mononuclear, but 3–5% were multinucleated (contained three
or more nuclei).
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). No TRAP-positive cells were observed
in control cultures incubated with either M-CSF alone or with M-CSF and
TGF-ß1 (0.1 ng/ml) without TNF-.
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, whereas overall cell numbers were unaffected
(Fig. 3 and legend). This suggests that
even those TRAP-positive cells formed by TNF- alone might be
dependent on endogenous TGF-ß in these cultures. Without TNF-, TGF
ß1 did not induce TRAP-positive cells (data not
shown).
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, was low (see Fig. 1
). We
have previously found that prolonged incubation in M-CSF before
addition of TRANCE similarly reduced osteoclastic differentiation,
compared with cultures to which TRANCE was added at the beginning of
the culture (26). It might be that differentiation into
macrophages is associated with resistance to osteoclast-induction.
Therefore, we tested the ability of TNF- and
TGF-ß1 to produce osteoclasts when added to
bone marrow cells immediately after these had been incubated for
24 h in M-CSF to remove stromal cells. Under these circumstances,
TNF- induced many more TRAP-positive cells comparable to cultures
similarly incubated early in TRANCE (see Ref. 26);
TGF-ß1 increased TRAP-positive cell formation.
Not only did TGF-ß1 increase the number of
TRAP-positive multinuclear cells formed and increase the proportion of
nuclei that were within strongly TRAP-positive cells (Figs. 4 and 5),
but TRAP-positive cells were induced at a lower concentration of
TNF- (1 ng/ml) than we had previously observed (Fig. 1). This
suggests that TGF-ß1 sensitized bone marrow
precursors to osteoclastic differentiation by TNF-. At least 90% of
the TRAP-positive multinuclear cells in these cultures, and some
TRAP-positive mononuclear cells, also expressed calcitonin receptors,
another marker for osteoclasts, by autoradiography (data not shown; see
Refs. 17, 26). Thus, a major phenotype of immature
mononuclear phagocytes incubated in TNF- with
TGF-ß1 is osteoclastic.
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to induce osteoclasts from resident peritoneal macrophages.
Both TRANCE and TNF- induced production of strongly TRAP-positive
cells (Fig. 6), of which 
3–5% were
multinuclear. OPG suppressed TRANCE-induced TRAP-positive cell
formation completely, but did not suppress TNF--induced
TRAP-positive cell production (there were 11 ± 4, 304 ±
172, and 210 ± 180 TRAP-positive cells/cm2
in cultures incubated with TNF- and OPG (100 ng/ml) for 8, 10, and
14 days, respectively).
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primes macrophages for activation of cytocidal capacity by
TNF-. IFN- is also known to suppress osteoclast formation in bone
marrow cultures (31). This latter action might occur
through effects of IFN- on osteoclast precursors, or stromal cells,
or both. To test whether IFN- has a direct inhibitory effect on
osteoclast-induction in uncommitted macrophage-osteoclast precursors,
we tested the effect of IFN- on osteoclast formation by TRANCE and
TNF- in cultures of bone marrow cells depleted of stromal cells by
incubation for 24 h in M-CSF. IFN- strongly suppressed
osteoclast induction by either agent (Fig. 7).
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, a proinflammatory cytokine, like TRANCE induced
osteoclasts, and because TGF-ß1, a macrophage
deactivator, augmented osteoclast formation by both agents, it seemed
possible that TRANCE might also be proinflammatory. Therefore, we
tested the ability of TRANCE to induce NO production in bone marrow and
peritoneal macrophages in the presence/absence of IFN-. TNF-
strongly activated NO production in both cell populations, but TRANCE
showed no effect whatsoever on either population (Figs. 8 and 9).
TRANCE was similarly unable to significantly increase the ability of
bone marrow cells to generate a respiratory burst (nmol
O2- per 106
cells; mean ± SD: M-CSF alone: 26.8 ± 3.8; with TNF-
(100 ng/ml): 188 ± 18.5; with TRANCE (100 ng/ml): 36.6 ±
10.6). Moreover, while inflammation in murine footpads was induced by
injection of 50 ng TNF-, TRANCE, like heat-treated TNF-, did not
increase perivascular leukocytes, even at the highest dose used (500
ng) compared with controls (Fig. 10).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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is a proinflammatory cytokine, capable of activating many
of the components of host defense, including the induction in
macrophages of cytocidal activity (18, 19).
Surprisingly, it was recently found to induce osteoclast formation from
bone marrow macrophages (17): bone-resorbing osteoclasts
and bacteriocidal macrophages seem phenotypically and functionally to
be very different cell types. If they are, then lineage regulation
requires additional signals. We found that
TGF-ß1 strongly promotes TRAP-positive cell
formation in response to TNF-, whereas IFN- activates NO
production while strongly inhibiting TRAP-positive cell formation.
IFN- and TGF-ß have opposing effects on diverse cellular functions
(25, 32, 33, 34, 35). Cytokines that signal, like IFN-, through
Janus kinase-STAT pathways (36, 37, 38) are generally
antagonistic to TGF-ß, which signals through SMADS-2 and -3
(39, 40), in the regulation of hemopoietic and immune-cell
function (25, 41). Transmodulation of TGF-ß/SMAD
signaling by the IFN-/STAT pathway might occur through the
IFN--induced SMAD-7, an antagonist SMAD (42). The
signaling systems might also cooperate for the expression of some genes
through interactions with p300 (43).
Whatever the mechanism by which IFN- and TGF-ß act and interact,
these cytokines clearly have a potent ability to modulate osteoclast vs
cytocidal macrophage differentiation. This suggests that the osteoclast
is an alternative destiny for mononuclear phagocyte precursors
activated by TNF-: while IFN- primes for cytocidal activity
(28, 44, 45, 46), TGF-ß1 promotes
osteoclast formation (Fig. 11).
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induces TRAP-positive cells even from M-CSF-dependent
bone marrow cells that have been allowed to differentiate into
macrophages for several days in culture (17), but we noted
that the proportion of such cells that become TRAP-positive is
substantially smaller than that observed if the precursors are
incubated in TNF- throughout. This is similar to our previous
experience of osteoclast-induction by TRANCE (26),
and consistent with the notion that precursors become increasingly
resistant to osteoclast-induction as macrophage differentiation
proceeds (26).
The ability of TNF- to induce osteoclast-like cell formation through
a direct effect on precursors might be the mechanism by which
inflammation leads to osteolysis in diseases such as rheumatoid
arthritis. Against this, OPG, the decoy receptor for TRANCE, was
recently reported to abolish bone erosion in adjuvant arthritis
(47). This supports the model in which TNF- stimulates
resorption through induction of TRANCE in osteoblastic cells
(48). The experiment (47) does not, however,
exclude a direct effect of TNF- on osteoclast precursors, because
TRANCE might be crucial for the induction of TNF- itself in adjuvant
arthritis.
Although the ability of TNF- to induce osteoclast-like cells
directly is a plausible explanation for inflammatory osteolysis,
TNF- is a major mediator of inflammation not only in bone, but in
all tissues. Moreover, the effect of TNF- is not limited to bone
marrow macrophage precursors; we found that peritoneal macrophages can
also be induced to form TRAP-positive cells. If mononuclear phagocytes
outside bone are susceptible to osteoclast-induction by TNF-, why
are not osteoclasts a common feature of inflammation? Presumably,
TNF- coexists in inflammatory exudates with other inflammatory
cytokines, such as GM-CSF, IL-4, and IFN-, which inhibit osteoclast
formation (49, 50, 51, 52). Because TNF- is proinflammatory,
whenever TNF- is present, so will be such inflammatory cytokines;
and when inflammation is succeeded by debridement and repair, levels of
TNF- will fall. However, whether or not TNF- induces osteoclast
formation in vivo, its ability to generate osteoclast-like cells in
vitro has implications for macrophage and osteoclast biology.
First, if induction of osteoclastic cells by TNF- in vitro reflects
the known ability of TNF- to activate macrophages, the corollary is
that TRANCE too might have a wider role as a macrophage activator. The
number and diversity of tissues that express TRANCE imply actions
beyond those described in lymphoid and bone biology. Moreover,
monocytes express RANK (53). What is the effect of
extraosseous TRANCE on these cells? One possibility is that, just as
TNF- is capable of activation of mononuclear phagocytes both to
cytocidal and osteoclastic phenotypes, TRANCE might share this
capacity. However, we found that TRANCE is unable to induce NO
production or heighten the potential for respiratory boost activity in
macrophages, and is not proinflammatory in vivo. TRANCE might therefore
have the special ability to activate macrophages without causing
inflammation. Its expression by stromal cells in bone and soft tissues
could then provide a mechanism by which macrophages are activated to
debride apoptotic cells and remodel tissues, including bone.
Second, the capacity of TGF-ß1 to inhibit
cytocidal activity in macrophages has led to its being considered to be
primarily a macrophage-deactivator (25). In this model,
its ability to facilitate formation of osteoclastic cells by TNF-
would be attributed to suppression of the alternative, cytocidal
lineage in precursors. However, TGF-ß1 also
promotes osteoclast formation by TRANCE (54, 55). Because
TRANCE, unlike TNF-, does not activate cytocidal functions in
mononuclear phagocytes, this suggests that
TGF-ß1 promotes formation of osteoclastic cells
not only by inhibiting cytocidal behavior, but also by actively
directing TNF--activation of precursors toward osteoclasts. The
corollary is that TGF-ß1 deactivation of
cytocidal to inflammatory or debriding macrophages
(21, 22, 23 ; see refs. 24, 25 for reviews)
might reflect active induction by TGF-ß1 of the
debriding phenotype in macrophages, equivalent to priming by IFN- of
macrophages for cytocidal activity. From this perspective, the
osteoclast could be envisaged as a special or activated version of
debriding macrophage, and TGF-ß1 as the
cytokine that determines the debriding lineage. Our data suggest that
the osteoclast is a mononuclear phagocyte, directed toward a debriding
function by TGF-ß1 and activated for this
function by TNF-/TRANCE.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Timothy J. Chambers, Department of Experimental Pathology, St. George’s Hospital Medical School, Cranmer Terrace, London SW17 ORE, U.K.
3 Abbreviations used in this paper: TRAP, tartrate-resistant acid phosphatase; TRANCE, TNF-related activation-induced cytokine; ODF, osteoclast differentiation factor; OPG, osteoprotegerin; OPGL, OPG ligand.
Received for publication March 27, 2000. Accepted for publication August 8, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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stimulates osteoclastic differentiation by a mechanism independent of the ODF/RANKL-RANK interaction. J. Exp. Med. 191:275.B ligand) mRNA and protein in skeletal and extraskeletal tissues. Bone 25:525.[Medline]
(TNF) by interferons. J. Clin. Invest. 93:1661.
) in the mouse. J. Invest. Dermatol. 91:353.[Medline]
inhibits formation of human osteoclast-like cells. J. Immunol. 137:3544.[Abstract]
and transforming growth factor-ß1 differently regulate fibronectin and laminin receptors of human differentiating monocytic cells. J. Immunol. 148:3912.[Abstract]
and is inhibited by transforming growth factor-ß. Eur. J. Immunol. 24:793.[Medline]
(IFN-). Clin. Exp. Immunol. 103:475.[Medline]
/STAT pathway. Nature 397:710.[Medline]
, PTH, PTHrP, and 1,25(OH)2D3. J. Bone Miner. Res. 14:1478.[Medline]
and ß induce osteoblastic cells to stimulate osteoclastic bone resorption. J. Immunol. 138:775.[Abstract]
. J. Bone Miner. Res. 1:469.[Medline]
inducing factor) is produced by osteoblasts and acts via granulocyte macrophage-colony stimulating factor and not via interferon- to inhibit osteoclast formation. J. Exp. Med. 185:1005., and prostaglandin E impact the osteoclast cell-forming potential of murine bone marrow macrophages. Endocrinology 136:2367.[Abstract]
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),
TRANCE (100 ng/ml; 
), or M-CSF alone (X). This experiment was
repeated twice with very similar results.
