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*
Department of Biochemistry, School of Dentistry, Showa University, Tokyo, Japan; and
Department of Oral Science, National Institute of Infectious Diseases, Tokyo, Japan
| Abstract |
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B), a
receptor of ODF. The survival of OCLs was enhanced by the addition of
each of sODF, M-CSF, and IL-1. sODF, as well as IL-1, activated NF-
B
and c-Jun N-terminal protein kinase (JNK) in OCLs. Like M-CSF and IL-1,
sODF stimulated the survival and multinucleation of prefusion
osteoclasts (pOCs) isolated from the coculture. When pOCs were cultured
on dentine slices, resorption pits were formed on the slices in the
presence of either sODF or IL-1 but not in that of M-CSF. A soluble
form of RANK as well as osteoprotegerin/osteoclastogenesis inhibitory
factor, a decoy receptor of ODF, blocked OCL formation and prevented
the survival, multinucleation, and pit-forming activity of pOCs induced
by sODF. These results suggest that ODF regulates not only osteoclast
differentiation but also osteoclast function in mice through the
receptor RANK. | Introduction |
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,25-dihydroxyvitamin D3,
parathyroid hormone, and IL-11 (3). The target cells of those
osteotropic factors are osteoblasts/stromal cells but not osteoclast
progenitors in the induction of osteoclasts in vitro (3). From these
results, we proposed a hypothesis that osteoblasts/stromal cells
express a common factor, osteoclast differentiation factor (ODF), in
response to those osteotropic factors. ODF appeared a
membrane-associated factor, since cell-to-cell contact between
osteoclast precursors and osteoblasts/stromal cells was prerequisite
for osteoclast formation. Thus, osteoclast precursors of the
monocyte-macrophage lineage recognize ODF through cell-to-cell
interaction with osteoblasts/stromal cells, then differentiate into
osteoclasts (3).
Osteoblasts/stromal cells also play an essential role in inducing
osteoclast function (osteoclast activation) (4). When purified
osteoclast-like cells (OCLs) formed in vitro were cultured on dentine
slices, they failed to form resorption pits (4). Osteoblasts/stromal
cells, simultaneously added, greatly enhanced the pit-forming activity
of OCLs through a mechanism involving cell-to-cell contact with OCLs
(4). OCLs rapidly died via spontaneously occurring apoptosis in the
absence of osteoblasts/stromal cells. The cytokines IL-1 and M-CSF were
shown to prolong the survival of purified OCLs (5). The activation of
NF-
B was involved in the IL-1-induced survival of OCLs (6). Using
pOCs obtained from the echistatin-treated coculture of murine
osteoblastic cells and bone marrow cells, we showed that both IL-1 and
M-CSF prolonged the survival and induced the multinucleation of pOCs,
but only IL-1 induced the pit-forming activity of pOCs, even in the
absence of osteoblasts/stromal cells (7). These results indicate that
some factors can be replaced with osteoblasts/stromal cells in the
induction of the survival, multinucleation, and activation of
osteoclasts.
The identical proteins osteoprotegerin (OPG) and osteoclastogenesis
inhibitory factor (OCIF), which inhibit osteoclast development in vitro
and in vivo, have recently been cloned independently (8, 9). OPG/OCIF
is a member of the TNF receptor family, but it does not have a
transmembrane domain, suggesting that OPG/OCIF functions as a
circulating factor. Subsequently, the cDNA encoding the binding
molecule of OPG/OCIF was isolated from an expression library of the
murine stromal cell line ST2, which supports OCL formation in coculture
with hemopoietic cells (10). The binding molecule of OPG/OCIF was a
membrane-associated protein of the TNF ligand family. This molecule
satisfied all of the criteria of ODF and was thus renamed ODF. ODF was
also found to be identical to TNF-related activation-induced cytokine
(TRANCE) and receptor activator of NF-
B ligand (RANKL), which were
independently cloned from murine T cell hybridomas and murine dendritic
cells, respectively (11, 12). Lacey et al. (13) also succeeded in the
molecular cloning of a ligand for OPG from an expression library of the
murine myelomonocytic cell line 32D. The OPG ligand (OPGL) was
identical to ODF (TRANCE/RANKL). The administration of OPGL (ODF) to
mice caused reduced bone volume and extreme hypercalcemia without a
significant increase in the number of osteoclasts, suggesting that ODF
is involved in the activation of osteoclasts as well (13). Fuller at
al. (14) also recently reported that TRANCE (ODF) is involved in the
osteoclast activation induced by osteoblastic cells treated with
parathyroid hormone. A soluble form of TRANCE induced a striking change
in the motility and spreading of isolated rat osteoclasts, and
inhibited their apoptosis (14). These results suggest that ODF is
necessary for the osteoblast-mediated activation of mature
osteoclasts.
The utilization of a soluble form of ODF (sODF) has allowed us to
elucidate the role of ODF in osteoclast function in more detail. In the
present study, we examined the effects of ODF on the survival,
multinucleation, and activation of osteoclasts in comparison with those
of M-CSF and IL-1. sODF, M-CSF, and IL-1 promoted the survival and
multinucleation of pOCs through their respective receptors. sODF and
IL-1, but not M-CSF, stimulated the pit-forming activity of OCLs. sODF,
as well as IL-1, activated NF-
B and c-Jun N-terminal protein kinase
(JNK) in OCLs. Not only OCIF but also a soluble form of RANK inhibited
all of the events induced by sODF. These results indicate that ODF
expressed by osteoblasts/stromal cells as a membrane-associated protein
is responsible for inducing not only osteoclast differentiation but
also osteoclast function.
| Materials and Methods |
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A recombinant murine sODF purified by affinity chromatography on
an OPG/OCIF-immobilized column and by gel filtration chromatography was
kindly provided by Snow Brand Milk Products (Tochigi, Japan). The
purity of sODF in this preparation was >95% in SDS polyacrylamide gel
electrophoresis. Recombinant human IL-1
, recombinant human M-CSF,
and murine IL-1 receptor antagonist (IL-1ra) were obtained from R&D
Systems (Minneapolis, MN). Echistatin was purchased from Sigma (St.
Louis, MO). Anti-human I
B
rabbit polyclonal Abs were purchased
from New England BioLabs (Lake Placid, NY). Anti-human Bcl-2,
Bcl-xL, and RelA (p65) rabbit polyclonal Abs were
purchased from Santa Cruz Biotechnology (Santa Cruz, CA). Anti-c-Fms
mAb was kindly provided by Dr. S-I. Nishikawa (Kyoto University, Kyoto,
Japan). Anti-human ß-actin mAb was obtained from Boehringer Mannheim
Biochemica (Mannheim, Germany).
Coculture system and enrichment of osteoclast-like cells
Osteoblasts obtained from the calvariae of newborn mice and bone
marrow cells obtained from the tibiae of male mice were cocultured in
MEM (Life Technologies, Grand Island, NY) containing 10% FBS,
1
,25-dihydroxyvitamin D3
(10-8 M) (Wako Pure Chemical, Osaka, Japan) and
PGE2 (10-6 M) (Sigma) in
100-mm-diameter dishes coated with collagen gels (Nitta Gelatin,
Osaka). OCLs were formed within 6 days in culture and were removed from
the dishes by treating with 0.2% collagenase (Wako). The purity of
OCLs in this fraction (crude OCL preparation) was about 5%. To further
purify the OCLs, the crude OCL preparation was replated on culture
dishes. After culture for 8 h, osteoblasts were removed with PBS
containing 0.001% pronase E (Calbiochem, La Jolla, CA) and 0.02% EDTA
according to the method described previously (15).
Mononuclear and binuclear pOCs were prepared as described previously
(16) with a slight modification. Cocultures of bone marrow cells and a
murine calvaria-derived osteoblastic cell line, KS4 (17), were
maintained in 100-mm-diameter dishes for 6 days as described above. The
KS4 cells were removed first from the coculture, using a mixture of
collagenase-dispase (Boehringer Mannheim), followed by washing three
times with 0.1% BSA in
MEM. pOCs were then released from the dish
with 30 nM echistatin. More than 90% of the cells in the pOC
preparation used in the present study were positive for TRAP.
Northern blot analysis
Total RNA was extracted from murine spleen cells, bone marrow cells, primary osteoblasts, purified OCLs, murine myoblastic C2C12 cells, and murine bone marrow-derived stromal ST2 cells using Trizol solution (Life Technologies). The total RNA (10 µg) was electrophoresed in 1.0% agarose-formaldehyde gels, and the RNA was transferred on nylon membrane filters (Hybond-N, Amersham International, Little Chalfont, U.K.). The membranes were hybridized for 15 h at 42°C with radioactive cDNA probes for murine RANK and murine TNF type I and type II receptors, which were cloned by RT-PCR and labeled using a multirandom primer oligonucleotide labeling kit (Takara Shuzo, Osaka, Japan). As an internal control, the membrane was rehybridized with a radioactive cDNA probe for mouse GAPDH. Each membrane was then exposed to an x-ray film.
EMSA and JNK assay
For the EMSA, nuclear extracts were prepared according to the
method described by Dignam et al. (18). The sequence of the
NF-
B-binding oligonucleotide used as a radioactive DNA probe was
5'-AGCTTGGGGACTTTCCGAG-3'. The DNA binding reaction was performed at
room temperature in a volume of 20 µl, which contained the binding
buffer (10 mM Tris/HCl (pH 7.5), 1 mM EDTA, 4% glycerol, 100 mM NaCl,
5 mM DTT, 100 mg/ml BSA), 3 µg of poly(dI-dC), 1 x
105 cpm of a 32P-labeled
probe, and 8 µg of nuclear proteins. After incubation for 15 min, the
samples were electrophoresed on native 5% acrylamide/0.25x TBE gels.
The gels were dried and exposed to an x-ray film. For the determination
of JNK activity, purified OCLs treated with sODF or IL-1 were washed
twice with ice-cold PBS, then lysed in a lysis buffer (20 mM Tris-HCl
(pH 7.5), 150 mM NaCl, 1 mM EDTA, 1 mM DGTA, 1% Triton X-100, 2.5 mM
sodium pyrophosphate, 1 mM ß-glycerophosphate, 1 mM
Na3VO4, 1 µg/ml
leupeptin, 1 mM PMSF). The JNK activity of the cell lysates was
determined using a stress-activated protein kinase (SAPK)/JNK kinase
assay kit (New England BioLabs).
Survival and cell fusion assays
The survival rate of OCLs was measured as reported previously (5, 19). After OCLs were purified, some of the cultures were subjected to TRAP staining. TRAP-positive MNCs containing more than 3 nuclei were counted as living OCLs. Other cultures were further incubated in the presence or absence of sODF. After incubation for indicated periods, the remaining OCLs were counted. To examine the effect of sODF on the fusion of osteoclasts, we replated pOCs (15,000 cells/well) on 96-well culture plates with or without various increasing concentrations of sODF. After culture for 18 h, the cells were fixed and stained for TRAP. Some cultures were also treated with IL-1ra (1 µg/ml), anti-c-Fms Ab (10 µg/ml), or OCIF (100 ng/ml). The number of TRAP-positive MNCs with more than 10 nuclei was counted as pOC-derived OCLs. Actin rings in pOC-derived OCLs were also visualized by rhodamine-conjugated phalloidin staining, as previously described (15). Results are expressed as the means ± SEM of three cultures.
Immunoblotting analysis and immunofluorescence microscopy
After purified OCL preparations were cultured for various
periods in the presence of ODF, the cells were washed twice with
ice-cold PBS and then lysed in a lysis buffer (20 mM Tris-HCl (pH 7.5),
150 mM NaCl, 1 mM EDTA, 0.5% Triton X-100, 10 µg/ml aprotinin, 20
µg/ml leupeptin, and 1 mM PMSF). The cell lysates (20 µg of
protein) were resolved by 10% SDS-PAGE and transferred onto
polyvinylidene difluoride (PVDF) membranes (Millipore, Bedford, MA).
After blocking with 2% BSA in TBST, the I
B
, Bcl-2 and
Bcl-xL Abs (1/1000 dilution) were added in TBST
containing 2% BSA and visualized by an enhanced chemiluminescence
assay using reagents from Amersham and exposed to an x-ray film. The
immunofluorescence analysis was done as described previously (6).
Anti-RelA (p65) Abs (1 µg/ml) was used for the immunostaining.
Pit formation assay
pOC preparations (15,000 cells/0.1 ml/well) were seeded on dentine slices (4-mm diameter) which had been placed in 96-well plates. After incubation for 2 h, dentine slices were transferred to 48-well plates (one slice/well) in the presence or absence of ODF. Pit formation by pOCs was determined after culture for 24 h. For the pit formation assay, cells were removed from dentine slices, and the resorbed area was stained with Mayers hematoxylin (15). The numbers of pits on the slices were counted.
Expression and purification of soluble RANK
A FLAG-tagged soluble form of RANK (sRANK) was generated by
cloning a PCR product encoding the RANK ectodomain (amino acids 1213)
into the EcoRI site of an expression vector that carries the
promoter region of human EF1
gene (pEF-BOS) (20). COS 7 cells were
transfected with the expression vectors (16.6 µg/100-mm-diameter
dish) by cationic liposomes (DMRIE-C, Life Technologies) according to
the manufactures recommendation. The supernatant was harvested
48 h later, passed through a 0.45-µm filter, incubated with
anti-FLAG M2 affinity gel (Kodak, New Haven, CT), and eluted with
FLAG peptide (250 µg/ml, Kodak) as outlined in the manufacturers
protocol. The eluant was dialyzed against PBS, and the protein
concentration was determined using a bicinchoninic acid (BCA) protein
assay kit (Pierce, Rockford, IL).
| Results |
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B (12). The
ligand-dependent NF-
B activation was also demonstrated by the
cotransfection of RANKL with RANK in human 293 cells and T cells (12).
We then examined whether sODF activates NF-
B in OCLs. sODF activated
NF-
B in OCLs in a dose-dependent manner (Fig. 2
B and the levels
of I
B
in OCLs after stimulation with sODF. sODF transiently
activated NF-
B in OCLs, and the maximal activation occurred at 30
min. The degradation of I
B
coincided with the activation of
NF-
B (Fig. 2
B activation, but it did not
affect at all the IL-1-induced NF-
B activation in the OCLs (Fig. 2
|
|
B is involved in the survival
of OCLs promoted by IL-1 (6). Like IL-1, sODF prolonged the survival of
OCLs in a dose-dependent manner (Fig. 4
|
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|
B and JNK by adding sRANK to purified OCLs.
Addition of sRANK significantly reduced the number of OCLs in a
dose-dependent manner (Fig. 7
B and JNK (Fig. 7
|
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| Discussion |
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The survival and multinucleation of pOCs induced by M-CSF, IL-1, and
sODF were inhibited by anti-c-Fms (M-CSF receptor) Ab, IL-1ra
(antagonist of IL-1 type 1 receptor), and OPG/OCIF (a decoy receptor of
ODF), respectively (Fig. 5
). OPG/OCIF specifically inhibited activation
of NF-
B and JNK in OCLs induced by sODF but not that induced by IL-1
(Figs. 2
and 3
). These results suggest that M-CSF, IL-1, and ODF have
similar effects on the survival and multinucleation of osteoclasts via
respective receptors. A soluble form of TNFR has been shown to inhibit
the activity of TNF-
and TNF-ß (25, 26, 27, 28). Here, sRANK inhibited the
OCL formation in bone marrow cultures treated with sODF together with
M-CSF and blocked the sODF-induced activation of NF-
B and JNK in
OCLs (Fig. 7
). Nakagawa et al. (21) recently reported that polyclonal
Abs against the extracellular domains of RANK induced OCL formation in
spleen cell cultures in the presence of M-CSF. This indicates that the
clustering of RANK is required for the RANK-mediated signal
transduction for osteoclastogenesis. In contrast, the Fab fragment of
anti-RANK Abs completely inhibited ODF-mediated osteoclastogenesis
(21). These results suggest that RANK is the sole receptor of ODF
responsible for inducing differentiation and activation of
osteoclasts.
We have reported that M-CSF is indispensable for both the proliferative
phase and the differentiation phase of osteoclast development (29). ODF
and M-CSF cannot be replaced by other cytokines in inducing osteoclast
differentiation. The present study shows that M-CSF and IL-1, as well
as ODF, prolonged the survival of OCLs and induced their fusion. ODF
and IL-1 but not M-CSF induced the pit-forming activity of purified
OCLs/pOCs in culture. These results suggest that ODF is the sole factor
for inducing osteoclast differentiation, but factors other than ODF are
also able to support the survival, fusion, and activation of mature
osteoclasts. Fig. 8
summarizes the role
of cytokines examined in this study in the regulation of osteoclast
differentiation and function.
|
B in OCLs, which coincided with the degradation of
I
B
(Fig. 2
B in OCLs, though it supported the survival and
fusion of OCLs/pOCs (our unpublished observation). These results
suggest that the survival and fusion of osteoclasts are not sufficient
for inducing osteoclast function. TRANCE (ODF) has been shown to induce the survival of dendritic cells through the up-regulation of Bcl-xL (23). It was also reported that targeting of both Bcl-xL and SV40 large T Ag to cells of the osteoclast lineage immortalized osteoclast precursors (30). These results suggest that antiapoptotic proteins such as Bcl-xL and Bcl-2 are involved in the survival of osteoclasts. However, neither Bcl-2 nor Bcl-xL in OCLs was up-regulated by sODF in our culture condition. IL-1 failed to induce the expression of Bcl-2 and Bcl-xL in OCLs (31). This suggests that ODF supports the survival of osteoclasts through a mechanism different from the up-regulation of Bcl-2 and Bcl-xL.
The activation of NF-
B has been shown to increase cellular
resistance to apoptosis (32, 33, 34, 35, 36). Using antisense oligodeoxynucleotides
to NF-
B (RelA/p65 and p50) and proteasome inhibitors that inhibit
the degradation of I
B, we have shown that the activation of NF-
B
is involved in the survival of OCLs promoted by IL-1 (6). The
activation of NF-
B appears to be also involved in the ODF-induced
survival of OCLs/pOCs. The precise role of JNK in apoptosis is
controversial. Strong activation of JNK was induced by
apoptosis-inducing stresses such as UV and hydrogen peroxide (37, 38, 39).
Using the knockout mice of the SEK1 gene, which encodes a direct
upstream kinase of JNK, SEK1-induced signals were shown to play a
protective role against various cytotoxic stimuli (40). TNF
receptor-associated factor (TRAF) 2 is a signal-transducing protein of
the TNF receptor family (39). The activation of JNK was impaired, but
the activation of NF-
B was induced in thymocytes obtained from
dominant negative (DN) TRAF2-transgenic mice and in embryonic
fibroblasts obtained from TRAF2-deficient mice (41, 42). These
thymocytes and fibroblasts were rather apoptotic in the presence of
TNF-
. Furthermore, thymocytes from I
B
DN and TRAF2 DN
double-transgenic mice were more sensitive to TNF-induced apoptosis
than those from normal mice and I
B
DN- or TRAF2 DN-transgenic
mice (43). Therefore, JNK-meditated signals appear to collaborate with
NF-
B in inducing the antiapoptotic action induced by sODF.
We previously showed that OCLs expressed IL-1 type 1 receptors (6). Xu et al. (44) reported that intense signals for IL-1 type I receptor mRNA were detected in active osteoclasts in an adjuvant arthritis model in rats, whereas mRNA of IL-1 type II receptor, which serves as a decoy receptor, was expressed preferentially in resting osteoclasts. Bone histological studies of OPG/OCIF knockout mice revealed that physiological bone resorption was regulated mainly by ODF and OPG/OCIF (45). IL-1 appears to be involved in pathological bone resorption, such as that observed in rheumatoid arthritis and periodontal bone diseases.
Recent studies indicate that the cytoplasmic tail of RANK interacts
with TRAF1, TRAF2, TRAF3, TRAF5, and TRAF6 (46, 47, 48, 49). Mapping of the
structural requirements for TRAF/RANK interaction revealed that
selective TRAF-binding sites clustered in two distinct domains of the
RANK cytoplasmic tail. In particular, TRAF6 interacted with the
membrane-proximal domain of the cytoplasmic tail distinct from binding
sites for TRAF1, -2, -3, and -5. When the TRAF6 interaction domain was
deleted, RANK-mediated NF-
B activation was completely inhibited, and
JNK activation was partially inhibited (48). N-terminal truncation of
TRAF6 (TRAF6 DN) also inhibited RANKL-induced NF-
B activation (48, 49). These results suggest that TRAF6 transduces a signal involved in
RANK-mediated activation of osteoclast function.
Double knockout mice of p50 (NF-
B1) and p52 (NF-
B2), subunits of
NF-
B, showed severe osteopetrosis because of the impaired osteoclast
differentiation (50, 51). The osteopetrotic disorder was cured by
normal bone marrow transplantation. These results indicate that
osteoclast progenitors are impaired in the deficient mice. sODF
activated NF-
B in the target cells including osteoclasts. This
suggests that the ODF-induced activation of NF-
B in osteoclast
progenitors also plays a crucial role in their differentiation into
osteoclasts. Further studies are necessary to elucidate the molecular
mechanism of the action of ODF in osteoclast differentiation and
function.
| Acknowledgments |
|---|
| Footnotes |
|---|
2 Address correspondence and reprint requests to Dr. Tatsuo Suda, Department of Biochemistry, School of Dentistry, Showa University 15-8 Hatanodai, Shinagawa-ku, Tokyo 142, Japan. E-mail address: ![]()
3 Abbreviations used in this paper: pOC, prefusion osteoclast-like cell; TRAP, tartrate-resistant acid phosphatase; ODF, osteoclast differentiation factor; OCL, osteoclast-like cell; OPG, osteoprotegerin; OCIF, osteoclastogenesis inhibitory factor; TRANCE, TNF-related activation-induced cytokine; RANK, receptor activator of NF-
B; L, ligand; sODF, soluble form of ODF; JNK, c-Jun N-terminal protein kinase; sRANK, soluble form of RANK; TRAF, TNF receptor-associated factor; DN, dominant negative; MNC, multinucleated cell; IL-1ra, IL-1 receptor antagonist; SAPK, stress-activated protein kinase; ERK, extracellular signal-regulated kinase; SEK1, SAPK-ERK kinase 1. ![]()
Received for publication January 20, 1999. Accepted for publication April 16, 1999.
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S. Kim, M. Yamazaki, L. A. Zella, N. K. Shevde, and J. W. Pike Activation of Receptor Activator of NF-{kappa}B Ligand Gene Expression by 1,25-Dihydroxyvitamin D3 Is Mediated through Multiple Long-Range Enhancers. Mol. Cell. Biol., September 1, 2006; 26(17): 6469 - 6486. [Abstract] [Full Text] [PDF] |
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A. R. Pettit, N. C. Walsh, C. Manning, S. R. Goldring, and E. M. Gravallese RANKL protein is expressed at the pannus-bone interface at sites of articular bone erosion in rheumatoid arthritis Rheumatology, September 1, 2006; 45(9): 1068 - 1076. [Abstract] [Full Text] [PDF] |
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E. Torikai, Y. Kageyama, M. Takahashi, M. Suzuki, T. Ichikawa, T. Nagafusa, and A. Nagano The effect of infliximab on bone metabolism markers in patients with rheumatoid arthritis Rheumatology, June 1, 2006; 45(6): 761 - 764. [Abstract] [Full Text] [PDF] |
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H. Ichikawa, A. Murakami, and B. B. Aggarwal 1'-Acetoxychavicol Acetate Inhibits RANKL-Induced Osteoclastic Differentiation of RAW 264.7 Monocytic Cells by Suppressing Nuclear Factor-{kappa}B Activation Mol. Cancer Res., April 1, 2006; 4(4): 275 - 281. [Abstract] [Full Text] [PDF] |
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H. Yoshida, K. Okamoto, T. Iwamoto, E. Sakai, K. Kanaoka, J.-P. Hu, M. Shibata, H. Hotokezaka, K. Nishishita, A. Mizuno, et al. Pepstatin A, an Aspartic Proteinase Inhibitor, Suppresses RANKL-Induced Osteoclast Differentiation. J. Biochem., March 1, 2006; 139(3): 583 - 590. [Abstract] [Full Text] [PDF] |
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D. Xu, S. Wang, W. Liu, J. Liu, and X. Feng A Novel Receptor Activator of NF-{kappa}B (RANK) Cytoplasmic Motif Plays an Essential Role in Osteoclastogenesis by Committing Macrophages to the Osteoclast Lineage J. Biol. Chem., February 24, 2006; 281(8): 4678 - 4690. [Abstract] [Full Text] [PDF] |
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H. Ichikawa and B. B. Aggarwal Guggulsterone Inhibits Osteoclastogenesis Induced by Receptor Activator of Nuclear Factor-{kappa}B Ligand and by Tumor Cells by Suppressing Nuclear Factor-{kappa}B Activation Clin. Cancer Res., January 15, 2006; 12(2): 662 - 668. [Abstract] [Full Text] [PDF] |
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B. Nardelli, L. Zaritskaya, W. McAuliffe, Y. Ni, C. Lincoln, Y. H. Cho, C. E. Birse, W. Halpern, S. Ullrich, and P. A. Moore Osteostat/Tumor Necrosis Factor Superfamily 18 Inhibits Osteoclastogenesis and Is Selectively Expressed by Vascular Endothelial Cells Endocrinology, January 1, 2006; 147(1): 70 - 78. [Abstract] [Full Text] [PDF] |
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H. Ha, J.-H. Lee, H.-N. Kim, H.-M. Kim, H. B. Kwak, S. Lee, H.-H. Kim, and Z. H. Lee {alpha}-Lipoic Acid Inhibits Inflammatory Bone Resorption by Suppressing Prostaglandin E2 Synthesis J. Immunol., January 1, 2006; 176(1): 111 - 117. [Abstract] [Full Text] [PDF] |
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H. Yamazaki and T. Sasaki Effects of osteoprotegerin administration on osteoclast differentiation and trabecular bone structure in osteoprotegerin-deficient mice J. Electron Microsc. (Tokyo), October 1, 2005; 54(5): 467 - 477. [Abstract] [Full Text] [PDF] |
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S. Yang, N. Takahashi, T. Yamashita, N. Sato, M. Takahashi, M. Mogi, T. Uematsu, Y. Kobayashi, Y. Nakamichi, K. Takeda, et al. Muramyl Dipeptide Enhances Osteoclast Formation Induced by Lipopolysaccharide, IL-1{alpha}, and TNF-{alpha} through Nucleotide-Binding Oligomerization Domain 2-Mediated Signaling in Osteoblasts J. Immunol., August 1, 2005; 175(3): 1956 - 1964. [Abstract] [Full Text] [PDF] |
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W. Liu, D. Xu, H. Yang, H. Xu, Z. Shi, X. Cao, S. Takeshita, J. Liu, M. Teale, and X. Feng Functional Identification of Three Receptor Activator of NF-{kappa}B Cytoplasmic Motifs Mediating Osteoclast Differentiation and Function J. Biol. Chem., December 24, 2004; 279(52): 54759 - 54769. [Abstract] [Full Text] [PDF] |
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M. L. Chaisson, D. G. Branstetter, J. M. Derry, A. P. Armstrong, M. E. Tometsko, K. Takeda, S. Akira, and W. C. Dougall Osteoclast Differentiation Is Impaired in the Absence of Inhibitor of {kappa}B Kinase {alpha} J. Biol. Chem., December 24, 2004; 279(52): 54841 - 54848. [Abstract] [Full Text] [PDF] |
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H T Hassan and M El-Sheemy Adult bone-marrow stem cells and their potential in medicine J R Soc Med, October 1, 2004; 97(10): 465 - 471. [Full Text] [PDF] |
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J. W. Lee, H. Y. Chung, L. A. Ehrlich, D. F. Jelinek, N. S. Callander, G. D. Roodman, and S. J. Choi IL-3 expression by myeloma cells increases both osteoclast formation and growth of myeloma cells Blood, March 15, 2004; 103(6): 2308 - 2315. [Abstract] [Full Text] [PDF] |
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X. Cheng, M. Kinosaki, M. Takami, Y. Choi, H. Zhang, and R. Murali Disabling of Receptor Activator of Nuclear Factor-{kappa}B (RANK) Receptor Complex by Novel Osteoprotegerin-like Peptidomimetics Restores Bone Loss in Vivo J. Biol. Chem., February 27, 2004; 279(9): 8269 - 8277. [Abstract] [Full Text] [PDF] |
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K. Suda, N. Udagawa, N. Sato, M. Takami, K. Itoh, J.-T. Woo, N. Takahashi, and K. Nagai Suppression of Osteoprotegerin Expression by Prostaglandin E2 Is Crucially Involved in Lipopolysaccharide-Induced Osteoclast Formation J. Immunol., February 15, 2004; 172(4): 2504 - 2510. [Abstract] [Full Text] [PDF] |
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T. Ikeda, M. Kasai, J. Suzuki, H. Kuroyama, S. Seki, M. Utsuyama, and K. Hirokawa Multimerization of the Receptor Activator of Nuclear Factor-{kappa}B Ligand (RANKL) Isoforms and Regulation of Osteoclastogenesis J. Biol. Chem., November 21, 2003; 278(47): 47217 - 47222. [Abstract] [Full Text] [PDF] |
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Z. Zhang, E. Jimi, and A. L. M. Bothwell Receptor Activator of NF-{kappa}B Ligand Stimulates Recruitment of SHP-1 to the Complex Containing TNFR-Associated Factor 6 That Regulates Osteoclastogenesis J. Immunol., October 1, 2003; 171(7): 3620 - 3626. [Abstract] [Full Text] [PDF] |
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D. V. Novack, L. Yin, A. Hagen-Stapleton, R. D. Schreiber, D. V. Goeddel, F. P. Ross, and S. L. Teitelbaum The I{kappa}B Function of NF-{kappa}B2 p100 Controls Stimulated Osteoclastogenesis J. Exp. Med., September 2, 2003; 198(5): 771 - 781. [Abstract] [Full Text] [PDF] |
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H. Ha, H. B. Kwak, S. K. Lee, D. S. Na, C. E. Rudd, Z. H. Lee, and H.-H. Kim Membrane Rafts Play a Crucial Role in Receptor Activator of Nuclear Factor kappa B Signaling and Osteoclast Function J. Biol. Chem., May 9, 2003; 278(20): 18573 - 18580. [Abstract] [Full Text] [PDF] |
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H. Yonou, N. Kanomata, M. Goya, T. Kamijo, T. Yokose, T. Hasebe, K. Nagai, T. Hatano, Y. Ogawa, and A. Ochiai Osteoprotegerin/Osteoclastogenesis Inhibitory Factor Decreases Human Prostate Cancer Burden in Human Adult Bone Implanted into Nonobese Diabetic/Severe Combined Immunodeficient Mice Cancer Res., May 1, 2003; 63(9): 2096 - 2102. [Abstract] [Full Text] [PDF] |
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K. Itoh, N. Udagawa, K. Kobayashi, K. Suda, X. Li, M. Takami, N. Okahashi, T. Nishihara, and N. Takahashi Lipopolysaccharide Promotes the Survival of Osteoclasts Via Toll-Like Receptor 4, but Cytokine Production of Osteoclasts in Response to Lipopolysaccharide Is Different from That of Macrophages J. Immunol., April 1, 2003; 170(7): 3688 - 3695. [Abstract] [Full Text] [PDF] |
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A. Gurlek, M. R. Pittelkow, and R. Kumar Modulation of Growth Factor/Cytokine Synthesis and Signaling by 1{alpha},25-Dihydroxyvitamin D3: Implications in Cell Growth and Differentiation Endocr. Rev., December 1, 2002; 23(6): 763 - 786. [Abstract] [Full Text] [PDF] |
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E M Gravallese Bone destruction in arthritis Ann Rheum Dis, November 1, 2002; 61(90002): ii84 - 86. [Abstract] [Full Text] [PDF] |
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K. Janssens and W. Van Hul Molecular genetics of too much bone Hum. Mol. Genet., October 1, 2002; 11(20): 2385 - 2393. [Abstract] [Full Text] [PDF] |
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M. Abe, K. Hiura, J. Wilde, K. Moriyama, T. Hashimoto, S. Ozaki, S. Wakatsuki, M. Kosaka, S. Kido, D. Inoue, et al. Role for macrophage inflammatory protein (MIP)-1alpha and MIP-1beta in the development of osteolytic lesions in multiple myeloma Blood, August 28, 2002; 100(6): 2195 - 2202. [Abstract] [Full Text] [PDF] |
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X. Li, N. Udagawa, K. Itoh, K. Suda, Y. Murase, T. Nishihara, T. Suda, and N. Takahashi p38 MAPK-Mediated Signals Are Required for Inducing Osteoclast Differentiation But Not for Osteoclast Function Endocrinology, August 1, 2002; 143(8): 3105 - 3113. [Abstract] [Full Text] [PDF] |
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T. Hayashi, T. Kaneda, Y. Toyama, M. Kumegawa, and Y. Hakeda Regulation of Receptor Activator of NF-kappa B Ligand-induced Osteoclastogenesis by Endogenous Interferon-beta (INF-beta ) and Suppressors of Cytokine Signaling (SOCS). THE POSSIBLE COUNTERACTING ROLE OF SOCSs IN IFN-beta -INHIBITED OSTEOCLAST FORMATION J. Biol. Chem., July 26, 2002; 277(31): 27880 - 27886. [Abstract] [Full Text] [PDF] |
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G.E. Wise, S. Frazier-Bowers, and R.N. D'Souza CELLULAR, MOLECULAR, AND GENETIC DETERMINANTS OF TOOTH ERUPTION Critical Reviews in Oral Biology & Medicine, July 1, 2002; 13(4): 323 - 335. [Abstract] [Full Text] [PDF] |
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D. Cappellen, N.-H. Luong-Nguyen, S. Bongiovanni, O. Grenet, C. Wanke, and M. Susa Transcriptional Program of Mouse Osteoclast Differentiation Governed by the Macrophage Colony-stimulating Factor and the Ligand for the Receptor Activator of NFkappa B J. Biol. Chem., June 7, 2002; 277(24): 21971 - 21982. [Abstract] [Full Text] [PDF] |
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B.-Y. Liu, P.-W. Wu, F. R. Bringhurst, and J.-T. Wang Estrogen Inhibition of PTH-Stimulated Osteoclast Formation and Attachment in Vitro: Involvement of Both PKA and PKC Endocrinology, February 1, 2002; 143(2): 627 - 635. [Abstract] [Full Text] [PDF] |
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J. M. Lean, K. Fuller, and T. J. Chambers FLT3 ligand can substitute for macrophage colony-stimulating factor in support of osteoclast differentiation and function Blood, November 1, 2001; 98(9): 2707 - 2713. [Abstract] [Full Text] [PDF] |
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T. Miyamoto, O. Ohneda, F. Arai, K. Iwamoto, S. Okada, K. Takagi, D. M. Anderson, and T. Suda Bifurcation of osteoclasts and dendritic cells from common progenitors Blood, October 15, 2001; 98(8): 2544 - 2554. [Abstract] [Full Text] [PDF] |
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S. Nilsson, S. Makela, E. Treuter, M. Tujague, J. Thomsen, G. Andersson, E. Enmark, K. Pettersson, M. Warner, and J.-A. Gustafsson Mechanisms of Estrogen Action Physiol Rev, October 1, 2001; 81(4): 1535 - 1565. [Abstract] [Full Text] [PDF] |
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K. Itoh, N. Udagawa, T. Katagiri, S. Iemura, N. Ueno, H. Yasuda, K. Higashio, J. M. W. Quinn, M. T. Gillespie, T. J. Martin, et al. Bone Morphogenetic Protein 2 Stimulates Osteoclast Differentiation and Survival Supported by Receptor Activator of Nuclear Factor-{kappa}B Ligand Endocrinology, August 1, 2001; 142(8): 3656 - 3662. [Abstract] [Full Text] [PDF] |
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M. Saika, D. Inoue, S. Kido, and T. Matsumoto 17{beta}-Estradiol Stimulates Expression of Osteoprotegerin by a Mouse Stromal Cell Line, ST-2, via Estrogen Receptor-{{alpha}} Endocrinology, June 1, 2001; 142(6): 2205 - 2212. [Abstract] [Full Text] [PDF] |
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S. Wei, S. L. Teitelbaum, M. W.-H. Wang, and F. P. Ross Receptor Activator of Nuclear Factor-{{kappa}}B Ligand Activates Nuclear Factor-{{kappa}}B in Osteoclast Precursors Endocrinology, March 1, 2001; 142(3): 1290 - 1295. [Abstract] [Full Text] [PDF] |
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B. O. Oyajobi, D. M. Anderson, K. Traianedes, P. J. Williams, T. Yoneda, and G. R. Mundy Therapeutic Efficacy of a Soluble Receptor Activator of Nuclear Factor {{kappa}}B-IgG Fc Fusion Protein in Suppressing Bone Resorption and Hypercalcemia in a Model of Humoral Hypercalcemia of Malignancy Cancer Res., March 1, 2001; 61(6): 2572 - 2578. [Abstract] [Full Text] |
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S. W. Fox, K. Fuller, K. E. Bayley, J. M. Lean, and T. J. Chambers TGF-{beta}1 and IFN-{gamma} Direct Macrophage Activation by TNF-{alpha} to Osteoclastic or Cytocidal Phenotype J. Immunol., November 1, 2000; 165(9): 4957 - 4963. [Abstract] [Full Text] [PDF] |
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A. Samura, S. Wada, S. Suda, M. Iitaka, and S. Katayama Calcitonin Receptor Regulation and Responsiveness to Calcitonin in Human Osteoclast-Like Cells Prepared in Vitro using Receptor Activator of Nuclear Factor-{kappa}B Ligand and Macrophage Colony-Stimulating Factor Endocrinology, October 1, 2000; 141(10): 3774 - 3782. [Abstract] [Full Text] [PDF] |
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N. Udagawa, N. Takahashi, H. Yasuda, A. Mizuno, K. Itoh, Y. Ueno, T. Shinki, M. T. Gillespie, T. J. Martin, K. Higashio, et al. Osteoprotegerin Produced by Osteoblasts Is an Important Regulator in Osteoclast Development and Function Endocrinology, September 1, 2000; 141(9): 3478 - 3484. [Abstract] [Full Text] [PDF] |
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H. Min, S. Morony, I. Sarosi, C. R. Dunstan, C. Capparelli, S. Scully, G. Van, S. Kaufman, P. J. Kostenuik, D. L. Lacey, et al. Osteoprotegerin Reverses Osteoporosis by Inhibiting Endosteal Osteoclasts and Prevents Vascular Calcification by Blocking a Process Resembling Osteoclastogenesis J. Exp. Med., August 21, 2000; 192(4): 463 - 474. [Abstract] [Full Text] [PDF] |
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K. Kanaoka, Y. Kobayashi, F. Hashimoto, T. Nakashima, M. Shibata, K. Kobayashi, Y. Kato, and H. Sakai A Common Downstream Signaling Activity of Osteoclast Survival Factors That Prevent Nitric Oxide-Promoted Osteoclast Apoptosis Endocrinology, August 1, 2000; 141(8): 2995 - 3005. [Abstract] [Full Text] [PDF] |
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D. L. Lacey, H. L. Tan, J. Lu, S. Kaufman, G. Van, W. Qiu, A. Rattan, S. Scully, F. Fletcher, T. Juan, et al. Osteoprotegerin Ligand Modulates Murine Osteoclast Survival in Vitro and in Vivo Am. J. Pathol., August 1, 2000; 157(2): 435 - 448. [Abstract] [Full Text] [PDF] |
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L. C. Hofbauer and A. E. Heufelder The Role of Receptor Activator of Nuclear Factor-{kappa}B Ligand and Osteoprotegerin in the Pathogenesis and Treatment of Metabolic Bone Diseases J. Clin. Endocrinol. Metab., July 1, 2000; 85(7): 2355 - 2363. [Full Text] |
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C. Capparelli, P. J. Kostenuik, S. Morony, C. Starnes, B. Weimann, G. Van, S. Scully, M. Qi, D. L. Lacey, and C. R. Dunstan Osteoprotegerin Prevents and Reverses Hypercalcemia in a Murine Model of Humoral Hypercalcemia of Malignancy Cancer Res., February 1, 2000; 60(4): 783 - 787. [Abstract] [Full Text] |
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K. Kobayashi, N. Takahashi, E. Jimi, N. Udagawa, M. Takami, S. Kotake, N. Nakagawa, M. Kinosaki, K. Yamaguchi, N. Shima, et al. Tumor Necrosis Factor {alpha} Stimulates Osteoclast Differentiation by a Mechanism Independent of the Odf/Rankl-Rank Interaction J. Exp. Med., January 17, 2000; 191(2): 275 - 286. [Abstract] [Full Text] [PDF] |
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K Fuller, J. Lean, K. Bayley, M. Wani, and T. Chambers A role for TGFbeta(1) in osteoclast differentiation and survival J. Cell Sci., January 7, 2000; 113(13): 2445 - 2453. [Abstract] [PDF] |
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W. C. Dougall, M. Glaccum, K. Charrier, K. Rohrbach, K. Brasel, T. De Smedt, E. Daro, J. Smith, M. E. Tometsko, C. R. Maliszewski, et al. RANK is essential for osteoclast and lymph node development Genes & Dev., September 15, 1999; 13(18): 2412 - 2424. [Abstract] [Full Text] |
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M. Katagiri, Y. Hakeda, D. Chikazu, T. Ogasawara, T. Takato, M. Kumegawa, K. Nakamura, and H. Kawaguchi Mechanism of Stimulation of Osteoclastic Bone Resorption through Gas6/Tyro 3, a Receptor Tyrosine Kinase Signaling, in Mouse Osteoclasts J. Biol. Chem., March 2, 2001; 276(10): 7376 - 7382. [Abstract] [Full Text] [PDF] |
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S. E. Lee, W. J. Chung, H. B. Kwak, C.-H. Chung, K. Kwack, Z. H. Lee, and H.-H. Kim Tumor Necrosis Factor-alpha Supports the Survival of Osteoclasts through the Activation of Akt and ERK J. Biol. Chem., December 21, 2001; 276(52): 49343 - 49349. [Abstract] [Full Text] [PDF] |
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N. K. Shevde, A. C. Bendixen, K. M. Dienger, and J. W. Pike Estrogens suppress RANK ligand-induced osteoclast differentiation via a stromal cell independent mechanism involving c-Jun repression PNAS, July 5, 2000; 97(14): 7829 - 7834. [Abstract] [Full Text] [PDF] |
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R. N. Pearse, E. M. Sordillo, S. Yaccoby, B. R. Wong, D. F. Liau, N. Colman, J. Michaeli, J. Epstein, and Y. Choi Multiple myeloma disrupts the TRANCE/ osteoprotegerin cytokine axis to trigger bone destruction and promote tumor progression PNAS, September 25, 2001; 98(20): 11581 - 11586. [Abstract] [Full Text] [PDF] |
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