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Department of Biochemistry (T.S., N.T., N.U., E.J.), School of Dentistry, Showa University, Shinagawa-ku, Tokyo 142-8555, Japan; and St. Vincent’s Institute of Medical Research (M.T.G., T.J.M.), University of Melbourne, Fitzroy, Victoria 3065, Australia
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 Top Abstract I. IntroductionII. Role of Osteoblasts/Stromal...III. New Members of...IV. Regulatory Mechanism in...V. Regulation of Human...VI. Summary and ConclusionReferences |
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I. Introduction |
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TopAbstractI. IntroductionII. Role of Osteoblasts/Stromal...III. New Members of...IV. Regulatory Mechanism in...V. Regulation of Human...VI. Summary and ConclusionReferences |
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,25-dihydroxyvitamin D3
[1,25(OH)2D3], PTH, and interleukin 11
(IL-11). Osteoclast precursors of the monocyte-macrophage lineage
recognize ODF/SOFA through cell-to-cell interaction with
osteoblasts/stromal cells, and then differentiate into osteoclasts.
Osteoblasts/stromal cells also play an essential role in the activation
of osteoclast function. We emphasize that the term
"osteoblasts/stromal cells" is an operational one, used for
convenience to describe those cells of the osteoblast lineage that have
been shown convincingly in vitro to determine osteoclast
formation. It is not certain in vivo which members of the
lineage cells are responsible. In vitro data suggest that
the osteoblast property is progressively lost with maturation of the
osteoblast lineage cells, and in vivo, it is not at all
likely that mature, synthesizing osteoblasts make any contribution to
osteoclast formation. Nor are osteocytes likely to do so, but likely
potential contributors are lining cells and early members of the
osteoblast lineage that are situated close to the endosteal surface.
Ultimately, the process of osteoclast formation is dependent on
hemopoietic precursors being presented to the appropriate
osteoblasts/stromal cells in an environment that provides appropriate
stimulatory factors. Recently, three laboratories independently cloned cDNAs encoding the identical proteins, giving it the names osteoprotegerin (OPG), osteoclastogenesis inhibitory factor (OCIF), and tumor necrosis factor (TNF) receptor-like molecule 1 (TR1). This protein inhibits osteoclast development in vitro and in vivo. In an attempt to adopt a uniform nomenclature for this important biological activity, we propose that the name of choice be "osteoprotegerin." OPG is a member of the TNF receptor family, but it does not have a transmembrane domain and possesses a signal sequence, suggesting that OPG functions as a secreted factor. Since OPG has the capacity to limit osteoclast formation, the ligand for this receptor was proposed to be the long-sought-after ODF/SOFA. Indeed, this hypothesis dictated the experiments carried out by the groups who subsequently identified a membrane-bound TNF-like ligand with the capacity to differentiate hematopoietic cells into functional osteoclasts. cDNA libraries from cell lines, which expressed specific binding sites for OPG, were screened by expression cloning approaches. As expected, the binding molecule of OPG was a membrane-associated protein of the TNF ligand family, which satisfied all the criteria of ODF/SOFA. In addition, ODF/SOFA was also able to maintain osteoclasts that had been induced by osteoblasts/stromal cells in an activated state. The discovery of this differentiation factor now opens a new era to investigate the molecular mechanism of osteoclast development and function.
This review article describes the role of osteoblasts/stromal cells in osteoclast development and function at a molecular level, especially focusing on the central role of members of the TNF receptor and ligand superfamilies. Because discoveries in this area have originated from several directions and by different research groups, nomenclature has rapidly become confusing; thus, we propose an approach to overcome this.
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II. Role of Osteoblasts/Stromal Cells in Osteoclast Differentiation and Function |
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TopAbstractI. IntroductionII. Role of Osteoblasts/Stromal...III. New Members of...IV. Regulatory Mechanism in...V. Regulation of Human...VI. Summary and ConclusionReferences |
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vß3), and the ability to form resorption pits on bone and dentine
slices. Some mouse stromal cell lines such as MC3T3-G2/PA6 and ST2
resemble calvarial osteoblasts and support osteoclastogenesis in
coculture with mouse spleen cells (10).
Experiments on the osteopetrotic op/op mouse model have
established that an osteoblast/stromal cell product, macrophage
colony-stimulating factor (M-CSF, also called CSF-1), is crucial for
osteoclast formation. The M-CSF gene of op/op mice cannot
code functionally active M-CSF protein due to an extra thymidine
insertion in the coding region of the M-CSF gene (11, 12).
Administration of recombinant human M-CSF restored impaired bone
resorption in op/op mice (13, 14). Calvarial osteoblasts
obtained from op/op mice failed to support osteoclast
development in cocultures with normal spleen cells, but the addition of
M-CSF to cocultures induced osteoclast formation in response to
1,25(OH)2D3 (15, 16, 17). These findings
indicate that M-CSF produced by osteoblasts/stromal cells plays an
essential role in osteoclast development.
After identification of the hemopoietic origin of osteoclasts, much
attention has been focused on the cell lineages of osteoclast
progenitors. Using ST2 cells as a stromal supportive cell line, it was
shown that, in addition to spleen cells and bone marrow cells,
peripheral blood mononuclear cells and alveolar macrophages acted as a
source of osteoclast precursors (18). Chambers et al. (19)
have established osteoclastogenic cell lines that express macrophage
phenotypes from H-2Kbts58 transgenic mice. Miyamoto et
al. (20) have also established the macrophage-like cell line C7
from a p53-deficient mouse. These cell lines differentiated into
osteoclasts when they were cocultured with stromal cells in the
presence of 1,25(OH)2D3, indicating that
osteoclasts are derived from cells of the monocyte/macrophage lineage.
Kurihara et al. (21) have shown that osteoclasts formed from
highly purified populations of CFU-GM (granulocyte and macrophage
colony-forming cells), the granulocyte-macrophage progenitors in
human marrow cultures. Hattersley et al. (22) have suggested
that mouse CFU-GM-derived cells also form osteoclasts in the coculture.
These results indicate that osteoclast precursors are derived from
cells in the monocyte-macrophage lineage, with CFU-GM as the earliest
identifiable precursor.
Findings after the disruption of the c-fos gene and PU.1 gene in mice supported the monocyte/macrophage origin of osteoclasts. Disruption of the protooncogene c-fos gives rise to severe osteopetrotic disorders in bone caused by a defect in osteoclast progenitors (23, 24). Transplantation of normal bone marrow cells into c-Fos(-/-) mice rescued the osteopetrosis (25). In addition, the number of F4/80- and Mac-2-positive macrophages was increased in bones of c-Fos(-/-) mice, suggesting that the lack of the c-fos gene causes a lineage shift between osteoclast and macrophage differentiation (25). In cocultures of osteoblasts and spleen cells, c-Fos(-/-) mouse-derived spleen cells failed to differentiate into osteoclasts. PU.1 is a myeloid- and B-cell-specific transcription factor, and PU.1(-/-) mice were found to be osteopetrotic (26). The development of both osteoclasts and macrophages was arrested in PU.1(-/-) mice. The osteopetrotic disorder of PU.1(-/-) mice was cured by transplantation of normal bone marrow cells into the mice. The absence of both macrophages and osteoclasts in PU.1(-/-) mice suggests that this transcription factor regulates the initial stage of myeloid differentiation. These results further support the notion that osteoclasts are derived from cells of the monocyte/macrophage lineage. However, the mechanism by which osteoclast progenitors enter and leave the circulation is not fully understood at present.
B. Stimulation of osteoclast differentiation by osteoblasts/stromal
cells
In the coculture system, cell-to-cell contact between
osteoblasts/stromal cells and hemopoietic cells was determined to be
indispensable for osteoclast development (5, 6, 7, 8, 9, 27). Additionally, the
osteoblasts/stromal cells have been identified as the target cells for
osteotropic hormones and cytokines other than M-CSF to induce
osteoclast development.
IL-6 exerts its activity via a cell surface receptor that consists of two components: a ligand-binding IL-6 receptor (IL-6R) and a non-ligand-binding but signal-transducing protein gp130 (28). A genetically engineered soluble IL-6R (sIL-6R), which lacks transmembrane and cytoplasmic domains, was determined to mediate the IL-6 signals through gp130 in response to IL-6 (28). Neither recombinant IL-6 nor sIL-6R alone induced osteoclast formation in the coculture, but osteoclasts were formed in response to IL-6 in the presence of sIL-6R (29). This suggests that a signal(s) mediated by gp130 is involved in osteoclast development. Cytokines such as IL-11, oncostatin M, and leukemia inhibitory factor, which transduce their signals through gp130, also induced osteoclast formation in coculture experiments (29, 30, 31). Additionally, in transgenic mice constitutively expressing human IL-6R, the expression of IL-6R in osteoblasts was clearly shown to be indispensable for induction of osteoclast recruitment (32). When osteoblasts obtained from human IL-6R-transgenic mice were cocultured with normal spleen cells, osteoclast formation was induced in response to human IL-6 without adding human sIL-6R. This suggests that cytokines that use gp130 as a common signal transducer act directly on osteoblasts/stromal cells but not on osteoclast progenitors to induce osteoclast formation. Osteoclasts are present in gp130 knockout mice because of the use of other available signaling pathways as described below.
One of the major messenger pathways used to induce osteoclast formation is cAMP, with the most widely studied agonist for this pathway being PTH. The target cells of PTH in inducing osteoclasts are also osteoblasts/stromal cells but not osteoclast progenitors in the coculture. Subclones of the human osteosarcoma cell line SaOS-2 were established to overexpress human PTH/PTH-related protein (PTHrP) receptor (PTHR1) under a heterologous promoter (33). Two cell lines, designated SaOS-2/4 and SaOS-4/3, which expressed functional recombinant PTHR1, supported osteoclast formation in response to PTH in the coculture with mouse spleen cells, while the parent SaOS-2 cells did not (33). Confirmation of the requirement for PTHR1 to be expressed on the osteoblast was achieved using cocultures established between osteoblasts and spleen cells from normal and PTHR1-deficient mice (34). It was shown that osteoclasts were formed in response to PTH in cocultures of spleen cells obtained from PTHR1(-/-) mice and normal calvarial osteoblasts (34). These results indicate that the expression of PTHR1 in osteoblasts/stromal cells is critical for PTH-induced osteoclast formation in the coculture.
The other known pathway used for osteoclast induction is that
stimulated by 1,25(OH)2D3. Kato and his
colleagues (35) have succeeded in producing
1,25(OH)2D3 receptor (VDR) knockout mice by
targeted disruption of the gene. Osteoblasts obtained from VDR(-/-)
mice failed to support osteoclast development in cocultures with normal
spleen cells in response to 1,25(OH)2D3 but
did so in response to PTH (36). In contrast, spleen cells from
VDR(-/-) mice differentiated into osteoclasts in coculture with
normal osteoblasts in response to
1,25(OH)2D3. These results suggest that the
signals mediated by VDR, like PTH and IL-11, are also transduced into
osteoblasts/stromal cells to induce osteoclast formation in the
coculture. The normal osteoclast formation in VDR(-/-) mice is
readily explained by the other available pathways (PTH, cytokines).
Thus, the signals induced by all bone-resorbing factors are
transduced in osteoblasts/stromal cells to induce osteoclast formation
(Fig. 1
). With this in mind, we have
proposed the hypothesis that osteoblasts/stromal cells express ODF,
which is a membrane-bound factor to promote differentiation of
osteoclast progenitors into osteoclasts through a mechanism involving
cell-to-cell contact (Fig. 1) (5, 6, 7, 8, 9). Chambers et al. (19)
also proposed that SOFA expressed by osteoblasts/stromal cells is
essentially involved in osteoclast differentiation. ODF and SOFA are
the terms applied to proteins that were assumed to be identical, and
reflecting the concept of contact-dependent promotion of osteoclast
formation.
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Wesolowski et al. (42) have also used echistatin (a snake
venom containing RGD-sequence) to isolate highly enriched mononuclear
or binuclear prefusion osteoclasts (pOCs) from cocultures of mouse bone
marrow cells and osteoblasts (MB 1.8 cells). These cells
expressed most of the characteristics of osteoclasts such as TRAP,
calcitonin receptors, vacuolar proton ATPase, and vitronectin
receptors. However, pOCs could only resorb bone when both MB 1.8 cells
and 1,25(OH)2D3 were present. These results
further support the hypothesis that cells of the osteoblast lineage
directly activate osteoclast function.
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III. New Members of the Tumor Necrosis Factor (TNF) Receptor and Ligand Families |
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,25(OH)2D3, PTH, PGE2, or IL-11
in the coculture. In vivo administration of OPG resulted in
an increase in bone mineral density and bone volume associated with a
decrease of active osteoclast number in normal and ovariectomized rats.
Serum Ca concentration was also decreased by injecting OPG into rats
(46, 47, 48). Finally, Tan et al. (49) also identified a new
member of the TNF receptor family named "TNF receptor-like molecule
1" (TR1) from a search of an expressed sequence tag data base. TR1
was found to be identical to OPG and inhibited osteoclast formation in
the coculture system, pit formation by osteoclasts, and bone resorption
in organ culture of fetal mouse long bones (50). For simplicity, and to
provide a uniform nomenclature system, we propose the name
"osteoprotegerin" (OPG) be adopted for the molecules that include
OCIF and TR1 (also see Fig. 4).
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(43, 45). In addition, OPG had two death domain homologous regions (D5,
D6) followed by a dmoain with a highly net positive charge (D7). D5 and
D6 share structural features with "death domains" of TNF receptor
p55, Fas, DR3, and TRAIL receptor, which mediate apoptotic signals.
Seven structural domains (D1–D7) of human OPG have been characterized
using various mutant proteins (52). The N-terminal portion of OPG
containing D1–D4 was sufficient to inhibit osteoclast formation in the
coculture, although the potency of the mutant protein that lacks D5–D7
was decreased to about 10% of that of the wild-type OPG. A
heparin-binding site was located in D7, and the affinity for heparin
did not correlate with the osteoclastogenesis-inhibitory activity. OPG
can exist as a monomer or dimer as a result of formation of a disulfide
bond using Cys400 present in D7. However, dimerization of
OPG was not necessary for biological activity of OPG since the
substitution of the Cys400 to Ser did not affect the
osteoclastogenic inhibitory activity of OPG. In addition, when the
transmembrane domain of Fas was inserted between D4 and D5 and the
mutant protein was expressed in the human kidney cell line 293-EBNA,
apoptosis was induced in the transfected cells (52). Although the
precise role of D5 and D6 of OPG is still not known, the death
domain-homologous regions are active in mediating apoptotic signals.
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TRAIL is a TNF-related ligand that induces apoptosis upon binding to its death domain-containing receptors, DR4 and DR5. Emery et al. (55) recently reported that OPG bound to TRAIL and inhibited TRAIL-induced apoptosis of Jurkat cells. They also showed that TRAIL blocked the osteoclastogenesis-inhibitory activity of OPG in the coculture. These results indicate a potential cross-regulatory mechanism involving OPG and TRAIL, which may also participate in the regulation of osteoclastic bone resorption.
B. Osteoclast differentiation factor (ODF) and stromal osteoclast
forming activity (SOFA)
1. ODF. As OPG was a member of the TNF receptor family, a
likely candidate for ODF/SOFA would be a membrane-bound ligand for this
receptor. Since ODF/SOFA should be expressed on the surface of ST2
cells after stimulation via 1,25(OH)2D3 and
dexamethasone, this cell line was assessed for the ability of OPG to
bind specifically to ST2 cells treated with
1,25(OH)2D3 and dexamethasone (45).
Expression cloning of the ligand for OPG was performed using a cDNA
library of ST2 cells. A cDNA clone with an open reading frame encoding
316 amino acid residues was isolated (56). The OPG-binding molecule was
a type II transmembrane protein of the TNF ligand family (Fig. 3A). When COS-7 cells transfected with
the OPG-binding molecule expression vector were fixed with
paraformaldehyde and cocultured with mouse spleen cells in the presence
of M-CSF, osteoclasts were formed on the fixed COS-7 cells. This
suggested that the OPG-binding molecule mediated cell-to-cell signals
responsible for osteoclastogenesis. A genetically engineered soluble
form of the OPG-binding protein together with M-CSF induced osteoclast
formation from spleen cells in the absence of osteoblasts/stromal
cells, which was abolished completely by simultaneously adding OPG
(Fig. 3B). Treatment of calvarial osteoblasts with the known
stimulators of osteoclast formation,
1,25(OH)2D3, PTH, PGE2, or
IL-11, up-regulated expression of mRNA of this molecule (56). From
these results, it was concluded that the OPG-binding molecule was ODF,
which mediates an essential signal to osteoclast progenitors for their
differentiation into osteoclasts. Thus, the OPG-binding molecule was
called "ODF." In contrast to the stimulatory actions of
1,25(OH)2D3 and dexamethasone on ODF mRNA
production, OPG mRNA levels were diminished, suggesting that the
regulation of OPG levels is also critical for osteoclastogenesis
induced by osteotropic factors.
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,25(OH)2D3, PTH,
PGE2, and IL-1 (57). These results clearly indicate that
bone resorption induced by these osteotropic factors is mediated by
ODF. 2. OPGL (OPG ligand). Lacey et al. (58) 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. Recombinant OPGL expressed by human fibroblasts existed in both membrane-associated and soluble forms (58). However, there is no evidence that the soluble form of OPGL (ODF) is present in the microenvironment of bone. A recombinant soluble form of OPGL (sOPGL) stimulated osteoclast development in bone marrow cultures in the presence of M-CSF, and it induced TRAP-positive colony formation supported by M-CSF in an agar culture of bone marrow cells. Pit-forming activity of osteoclasts isolated from newborn rats was also stimulated by sOPGL. When sOPGL was injected into mice twice a day for 3 days, hypercalcemia was induced although the number of osteoclasts was almost identical to those of untreated mice (58). These results indicate that OPGL stimulates not only osteoclast differentiation but also osteoclast function. Recently, Kong et al. (59) have succeeded in generating OPGL knockout mice. OPGL(-/-) mice exhibited typical osteopetrosis with total occlusion of bone marrow space within endosteal bone. OPGL(-/-) mice lack osteoclasts but have normal osteoclast progenitors that can differentiate into functionally active osteoclasts when cocultured with normal osteoblasts/stromal cells. In addition, OPGL(-/-) mice completely lack lymph nodes and have a defect in thymocyte differentiation. These results suggest that OPGL is an absolute requirement for osteoclast development, and it plays an important role in T cell differentiation as well.
The molecular cloning of ODF/OPGL revealed that this molecule was
identical to TRANCE (TNF-related activation-induced cytokine) and RANKL
[receptor activator of nuclear factor (NF)-
B ligand], which were
independently identified by other groups as a novel member of the TNF
ligand family (Fig. 4
).
3. TRANCE. TRANCE was cloned during a search for apoptosis-regulatory genes in murine T cell hybridomas (60). Northern blot analysis showed that thymus and lymph nodes expressed high levels of TRANCE. A recombinant soluble form of TRANCE induced activation of c-Jun N-terminal kinase (JNK) in T lymphocytes. The putative TRANCE receptor was detected on mature dendritic cells (61). Signaling by the receptor for TRANCE appeared to be dependent on TNF receptor-associated factor 2 (TRAF2), since JNK induction was impaired in thymocytes from transgenic mice overexpressing the dominant negative TRAF2 protein. TRANCE inhibited apoptosis of mouse and human dendritic cells in vitro with up-regulation of Bcl-xL expression (61). The increase in the survival of dendritic cells induced by TRANCE was accompanied by an increase in dendritic cell-mediated T cell proliferation in a mixed leukocyte reaction.
4. RANK (receptor activator of NF-B) and its ligand
(RANKL). Anderson et al. (62) cloned a new member of
the TNF receptor family termed "RANK" from a cDNA library of human
dendritic cells. The mouse homolog was also isolated from the fetal
mouse liver cDNA library. The mouse RANK cDNA encoded a type I
transmembrane protein of 625 amino acid residues. Like OPG, this
protein bears four extracellular cysteine-rich domains. Northern blot
analysis of human tissue RNAs revealed ubiquitous expression of RANK
mRNA with highest levels in the skeletal muscle and thymus. RANK failed
to bind other members of the TNF ligand family such as Fas ligand, CD27
ligand, CD30 ligand, CD40 ligand, TNF, or TRAIL. In searching for
the binding molecule of RANK, a RANK ligand (RANKL) was cloned from a
cDNA library of murine thymoma EL40.5 cells and found to be identical
to TRANCE (62). A soluble form of RANKL augmented the ability of
dendritic cells to stimulate T cell proliferation in a mixed lymphocyte
reaction and increased the survival of RANK-positive T cells.
Darnay et al. (63) reported that TRAF2, TRAF5, and TRAF6
interacted with RANK at the C-terminal 85-amino acid tail. Furthermore,
overexpression of RANK in human embryonic kidney 293 cells stimulated
JNK and nuclear factor (NF)-B activation. When the C-terminal
tail necessary for the TRAF binding was deleted, the truncated RANK
receptor was still capable of stimulating JNK activity but not NF-B.
This suggests that interaction with TRAFs is necessary for NF-B
activation but not for the activation of the JNK pathway. Wong et
al. (64) showed that TRAF6 was also associated with the N-terminal
portion of the cytoplasmic domain in addition to the C-terminal tail in
the TRANCE receptor (RANK). Dominant negative forms of TRAF2, TRAF5,
and TRAF6 inhibited TRANCE receptor (RANK)-mediated NF-B activation
in the cotransfected cells (64). These results suggest that
RANKL/TRANCE directs differentiation and activation of osteoclasts
through RANK by stimulating NF-B via TRAFs. These findings appear to
be contradictory to the finding that the JNK induction was impaired in
thymocytes prepared from dominant negative TRAF2 transgenic mice (61).
Further studies are needed for elucidating the signaling pathway of
RANK.
5. Nomenclature. The ligand, receptor, and decoy receptor of
the new TNF receptor-ligand family members are schematically summarized
in Fig. 4. Thus, ODF, OPGL, TRANCE, and RANKL are the same molecule
important for development and function of T cells and dendritic cells
as well as osteoclasts. RANK appears to be the transmembrane-signaling
receptor for ODF/OPGL/TRANCE/RANKL. OCIF/OPG/TR1 is a soluble receptor
for ODF/OPGL/TRANCE/RANKL and appears to function as a decoy receptor.
These TNF-related ligands and receptors (membrane-bound and secreted)
have a diverse range of functions and effects on cells other than
osteoclasts and osteoblasts.
In the light of these other actions and their relatively wide
distribution, the nomenclature of these molecules needs to be reviewed.
To date there is only one report describing the putative signaling
receptor, RANK, and we believe that this name should be used; it should
be noted that an identical molecule that fulfills RANK’s function has
been proposed as the TRANCE receptor (Fig. 4) (60, 63). The ligand for
RANK has been described as ODF, OPGL, TRANCE, and RANKL, and in
proposing RANKL as the preferred nomenclature for this molecule we took
into consideration its actions and distribution. The use of ODF implies
that its biological actions are specific to bone. While such a name
might be attractive to the bone biology field, it is unlikely that ODF
would be universally adopted, given its production by lymphocytes, its
action on T lymphocytes and dendritic cells, and possible functions in
other tissues. Use of OPGL would indicate that the molecule exerts its
biological actions exclusively by binding to OPG, but OPG also binds to
TRAIL (55). Furthermore, OPG appears to function as a decoy receptor
and, as such, may have hitherto unrecognized TNF-related ligands. The
acronym, TRANCE, derives from TNF-related activation-induced cytokine,
suggesting that this molecule is expressed only after activation of
cells. However, there is ample evidence for constitutive expression of
this ligand, which may be stimulated further (56, 58, 62).
We have several reasons for proposing that RANKL be the preferred name:
1) this molecule is to date the only ligand identified for the
membrane-bound signaling receptor, RANK; 2) it does not imply a unique
tissue specificity or action; 3) it accurately describes postreceptor
signaling actions, i.e., activating NF-B. Further, the
commercial availability of the soluble ligand, sRANKL, is giving rise
rapidly to wide usage of this term. On the basis of these reasons, we
use the names of OPG, RANKL, and RANK subsequently in this review
article (Fig. 4).
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IV. Regulatory Mechanism in Osteoclast Development and Function |
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TopAbstractI. IntroductionII. Role of Osteoblasts/Stromal...III. New Members of...IV. Regulatory Mechanism in...V. Regulation of Human...VI. Summary and ConclusionReferences |
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In the coculture system, the 6-day culture period can be separated into
two phases: the first 4 days in which proliferation of osteoclast
progenitors primarily occurs, and the final 2 days, in which their
differentiation into osteoclasts is predominant (65). When hydroxyurea
was added to the coculture for the first 4 days, no TRAP-positive cells
appeared on day 6 even in the presence of
1,25(OH)2D3. In contrast, adding hydroxyurea
to the cocultures during the final 2 days completely inhibited
proliferation of osteoclast progenitors but did not affect their
differentiation into osteoclasts in response to
1,25(OH)2D3. To confirm the involvement of
M-CSF in osteoclast development, normal spleen cells were cocultured
with osteoblasts derived from op/op mice (65). When M-CSF
was added throughout the 6-day coculture period, osteoclasts were
formed in response to 1,25(OH)2D3. However,
the lack of M-CSF either for the first 4 days or for the final 2 days
failed to result in osteoclast formation. These results confirm that
M-CSF is indispensable for both the proliferative phase and the
differentiation phase of osteoclast development (Fig. 5). Similarly, Biskobing et
al. (66) showed that M-CSF plays important roles in proliferation
and differentiation of osteoclast progenitors in mouse bone marrow
cultures.
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B. Regulatory mechanism of RANKL action on osteoclast function
When osteoblasts/stromal cells were removed from the coculture,
osteoclasts rapidly died within 48 h by spontaneously occurring
apoptosis (69). Among several cytokines and hormones examined, IL-1 and
M-CSF stimulated the survival of purified osteoclasts (Fig. 5) (70). To
elucidate further the regulation of fusion and function of osteoclasts
by IL-1 and M-CSF, pOCs were isolated using echistatin from cocultures
of mouse osteoblastic cells (MB 1.8 cells) and bone marrow cells. pOCs
spontaneously died within 48 h. Both IL-1 and M-CSF potentiated
survival and fusion of pOCs through their respective receptors (71).
The effects of IL-1 on pOCs were inhibited by the naturally occurring
inhibitor of IL-1, IL-1 receptor antagonist (IL-1ra), but not by a
monoclonal antibody against M-CSF receptor (c-Fms), AFS98. The
anti-c-Fms antibody (AFS98) inhibited M-CSF-induced effects on pOCs but
not IL-1-induced effects. Interestingly, resorption pit-forming
activity of pOCs placed on dentine slices was induced by adding IL-1
even in the absence of osteoblasts/stromal cells. M-CSF failed to
induce pit formation in the pOC culture performed on dentine slices. As
described above, enriched osteoclasts prepared from the coculture
failed to form resorption pits. Pit-forming activity of enriched
osteoclasts was markedly enhanced by adding IL-1, but not by M-CSF,
even in the absence of osteoblasts/stromal cells. Thus, it is concluded
that both IL-1 and M-CSF stimulate survival and fusion of pOCs, but
only IL-1 treatment leads to osteoclasts that are active in resorption
(Fig. 5). These results suggest that IL-1 might play a role as a real
potentiator of osteoclast activation in inflammatory bone diseases.
Survival of purified osteoclasts was also enhanced by adding sRANKL
(72). Treatment of purified osteoclasts with OPG suppressed the
survival of osteoclasts supported by sRANKL but not that by IL-1 or
M-CSF. Like IL-1 and M-CSF, sRANKL stimulated the survival and fusion
of pOCs. In addition, sRANKL induced the resorbing activity of pOCs.
These results indicate that both RANKL and IL-1 lead to enhanced
osteoclast function even in the absence of osteoblasts/stromal cells
(Fig. 5). This notion was confirmed by the experiments using osteoclast
preparations in which osteoblasts were completely absent. Bone marrow
cells were cultured on collagen gel-coated dishes in the presence of
sRANKL and M-CSF but in the absence of osteoblasts/stromal cells.
Osteoclasts formed were collected by collagenase digestion. When these
osteoclasts were placed on dentine slices, they rapidly underwent
apoptosis without forming resorption pits. M-CSF, IL-1, and sRANKL all
prolonged the survival of those osteoclasts, but only sRANKL and IL-1
induced the pit-forming activity. When primary osteoblasts were added
to similarly prepared osteoclasts, resorption pits were formed.
Bone-resorbing factors such as 1,25(OH)2D3,
PTH, and IL-11 enhanced their pit formation only in the presence of
osteoblasts (73). Osteoblasts prepared from op/op mice also
induced pit-forming activity of osteoclasts, which was completely
inhibited by adding OPG. These results support the hypothesis that
osteoblasts/stromal cells activate osteoclast function through RANKL as
a membrane-associated factor. RANKL can be replaced with IL-1 to induce
survival, fusion, and activation of osteoclasts. However, IL-1 could
not support differentiation of osteoclast precursors into pOCs even in
the presence of M-CSF, when osteoblasts/stromal cells were absent (Fig. 5). These results also suggest that RANKL is involved in physiological
bone resorption, whereas IL-1 is involved in pathological bone
resorption such as rheumatoid arthritis and periodontitis. Although
RANKL has been shown recently to increase resorption by isolated rat
osteoclasts (74), the question of activation of mature osteoclasts is
more precisely addressed by using a culture system in which no
continued osteoclast formation takes place. We made use of osteoclasts
generated by such a method to determine that the effects of RANKL in
mature osteoclasts might result from prolongation of cell survival, as
well as a signal-mediated effect on osteoclast activity. Formation and
activation of osteoclasts cannot be easily distinguished in
vivo in mammals because the single factor, RANKL, expressed by
osteoblasts/stromal cells, carries out the two aspects of osteoclasts
(osteoclast differentiation and function).
C. Signals induced by IL-1 and RANKL in osteoclasts
An electrophoretic mobility shift assay revealed that IL-1
transiently activated NF-B in the nuclei of purified osteoclasts,
and the maximal activation occurred at 30 min after IL-1 addition (70).
Osteoclasts formed in the cocultures indeed have IL-1 type I receptors
(75). The degradation of I-B, which forms a complex with NF-B
and keeps the complex in the cytoplasm, coincided with the activation
of NF-B. The immunocytochemical study revealed that p65, a subunit
of NF-B, was translocated from the cytoplasm into almost all of the
nuclei of the multinucleated osteoclasts. Pretreatment of osteoclasts
with proteasome inhibitors or antisense oligodeoxynucleotides to p65
and p50 of NF-B prevented the survival of osteoclasts supported by
IL-1 (75). These results indicate that IL-1 promotes the survival of
osteoclasts through NF-B activation (Fig. 6). Northern blot analysis showed that
osteoclasts formed in the cocultures strongly expressed RANK mRNA (72).
Treatment of purified osteoclasts with sRANKL activated NF-B within
30 min, which was accompanied by the degradation of I-B. IL-1 and
sRANKL also activated JNK within 30 min in the purified osteoclasts.
These results suggest that the activation of NF-B and JNK in
osteoclasts by IL-1 and sRANKL results in induction of osteoclast
activation (Fig. 6). Bcl-xL expression remained unchanged in the
purified osteoclasts treated with RANKL, suggesting that a factor(s)
other than Bcl-xL is involved in the RANKL-induced survival of
osteoclasts.
|
B. The double-knockout mice developed osteopetrosis
because of a defect in osteoclast differentiation. The osteopetrotic
phenotype was rescued by bone marrow transplantation, indicating that
the osteoclast progenitors were impaired. Osteoclasts were totally
absent, but the number of Mac-2-positive macrophages was rather
increased in bone tissues from the double-knockout mice. These results
suggest that p50 and p52 can be replaced with each other in dimer
formation with p65 in osteoclast precursors. RANKL has been reported to
activate NF-B in the target cells (62), and we have also determined
this in the osteoclast (72). These results suggest that the
RANKL-induced activation of NF-B in osteoclast progenitors also
plays a crucial role in their differentiation into osteoclasts. It is
also conceivable that transcription factors other than NF-B are
regulated by RANK-mediated signals in osteoclast precursors and mature
osteoclasts. |
V. Regulation of Human Osteoclast Development |
|---|
|
TopAbstractI. IntroductionII. Role of Osteoblasts/Stromal...III. New Members of...IV. Regulatory Mechanism in...V. Regulation of Human...VI. Summary and ConclusionReferences |
|---|
,25(OH)2D3 and dexamethasone. In their
experiments, addition of human M-CSF to the coculture was essential to
induce human osteoclasts because UMR-106 and ST2 cells produce rat and
mouse M-CSF, respectively, which do not bind to human M-CSF receptors
(c-Fms). This finding also suggested that rat and mouse RANKL can act
on human cells as well. We also confirmed that the human osteoblastic
cell line, SaOS-4/3, which constitutively expressed functionally active
PTH receptors, supported human osteoclast formation in response to PTH
and dexamethasone in coculture with human peripheral blood mononuclear
cells (PBMCs) (33). Antihuman M-CSF antibody inhibited both mouse and
human osteoclast formation in coculture with SaOS-4/3 cells. These
results are consistent with the finding of Flanagan and her colleagues
(79, 80) who demonstrated a critical role of M-CSF in human osteoclast
formation as well.
Treatment of human PBMCs with mouse sRANKL and human M-CSF together
with dexamethasone induced human osteoclasts (Fig. 7) (81). OPG inhibited osteoclast
formation from human PBMCs that was supported either by SaOS-4/3 cells
or by sRANKL plus human M-CSF. PTH induced expression of RANKL mRNA by
SaOS-4/3 cells, and this was not affected by adding dexamethasone
(82). These results suggest that nonadherent cells in human
PBMCs produce an inhibitory factor(s) against human
osteoclastogenesis, production of which is down-regulated by
dexamethasone. When osteoclasts were generated from human PBMCs that
had been purified on a Ficoll gradient, sRANKL and M-CSF were effective
without the need for dexamethasone (83). Granulocyte-macrophage
colony-stimulating factor (GM-CSF) has been shown to be an important
factor for osteoclast formation in human bone marrow cultures (3, 21).
However, as in the case of mouse osteoclast formation, GM-CSF strongly
inhibited human osteoclast formation induced by sRANKL and M-CSF (Fig. 7 and Ref. 33). This suggests that GM-CSF stimulates proliferation of
osteoclast progenitors but inhibits their differentiation into
osteoclasts. These results also indicate that regulatory mechanisms of
human osteoclast formation are essentially the same as those of mouse
osteoclast formation. Regulation of human osteoclast formation and
function can be deduced from the findings obtained from the mouse
system.
|
|
VI. Summary and Conclusion |
|---|
|
TopAbstractI. IntroductionII. Role of Osteoblasts/Stromal...III. New Members of...IV. Regulatory Mechanism in...V. Regulation of Human...VI. Summary and ConclusionReferences |
|---|
). Although many attempts have been made
to elucidate the mechanism of the so-called "microenvironment
provided by osteoblasts/stromal cells," (5, 6, 7, 8) it has remained
an open question until OPG and its binding molecule were cloned. The
serial discovery of the new members of the TNF receptor-ligand family
members has confirmed the idea that osteoclast differentiation and
function are regulated by osteoblasts/stromal cells. RANKL, which has
also been called ODF, TRANCE, or OPGL, is a member of the TNF ligand
family. Expression of RANKL mRNA in osteoblasts/stromal cells is
up-regulated by osteotropic factors such as
1,25(OH)2D3, PTH, and IL-11. Osteoclast
precursors express RANK, a TNF receptor family member, recognize RANKL
through cell-to-cell interaction with osteoblasts/stromal cells, and
differentiate into pOCs in the presence of M-CSF. RANKL is also
involved in the survival and fusion of pOCs and activation of mature
osteoclasts. OPG, which has also been called OCIF or TR1, is a soluble
receptor for RANKL and acts as a decoy receptor in the RANK-RANKL
signaling system (Fig. 8).
|
). Osteoblasts/stromal
cells can now be replaced with RANKL and M-CSF in dealing with the
whole life of osteoclasts. RANKL, RANK, and OPG are three key molecules
that regulate osteoclast recruitment and function. Further studies on
these key molecules will elucidate the molecular mechanism of the
regulation of osteoclastic bone resorption. This line of studies will
establish new ways to treat several metabolic bone diseases caused by
abnormal osteoclast recruitment and functions such as osteopetrosis,
osteoporosis, metastatic bone disease, Paget’s disease, rheumatoid
arthritis, and periodontal bone disease.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
|
References |
|---|
|
TopAbstractI. IntroductionII. Role of Osteoblasts/Stromal...III. New Members of...IV. Regulatory Mechanism in...V. Regulation of Human...VI. Summary and ConclusionReferences |
|---|
,25-dihydroxyvitamin D3 in osteoclast
differentiation and function. Methods Enzymol 282:223–235[Medline]
,25-dihydroxyvitamin D3,
prostaglandin E2 or parathyroid hormone in the
microenvironment of bone. Biochem Biophys Res Commun 246:337–341[CrossRef][Medline]
B (RANK). J Biol Chem 273:20551–20555B
activation by the TRANCE receptor. J Biol Chem 273:28355–28359 maintain the survival of
osteoclast-like cells. Endocrinology 136:808–811[Abstract]
activates an NF-B-like factor in
osteoclast-like cells. J Biol Chem 271:4605–4608B is involved in the survival of
osteoclasts promoted by interleukin-1. J Biol Chem 273:8799–8805B in osteoclast and B-cell development. Genes Dev 11:3482–3496B1 and NF-B2. Nat
Med 3:1285–1289[CrossRef][Medline]
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|
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|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
Y. Nakamichi, N. Udagawa, Y. Kobayashi, M. Nakamura, Y. Yamamoto, T. Yamashita, T. Mizoguchi, M. Sato, M. Mogi, J. M. Penninger, et al. Osteoprotegerin Reduces the Serum Level of Receptor Activator of NF-{kappa}B Ligand Derived from Osteoblasts J. Immunol., January 1, 2007; 178(1): 192 - 200. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
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|
|
|
|
 |
|
 K. Sato, A. Suematsu, K. Okamoto, A. Yamaguchi, Y. Morishita, Y. Kadono, S. Tanaka, T. Kodama, S. Akira, Y. Iwakura, et al. Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction J. Exp. Med., November 27, 2006; 203(12): 2673 - 2682. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Mochizuki, M. Takami, T. Kawawa, R. Suzumoto, T. Sasaki, A. Shiba, H. Tsukasaki, B. Zhao, R. Yasuhara, T. Suzawa, et al. Identification and Characterization of the Precursors Committed to Osteoclasts Induced by TNF-Related Activation-Induced Cytokine/Receptor Activator of NF-{kappa}B Ligand J. Immunol., October 1, 2006; 177(7): 4360 - 4368. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 T. Kawai, T. Matsuyama, Y. Hosokawa, S. Makihira, M. Seki, N. Y. Karimbux, R. B. Goncalves, P. Valverde, S. Dibart, Y.-P. Li, et al. B and T Lymphocytes Are the Primary Sources of RANKL in the Bone Resorptive Lesion of Periodontal Disease Am. J. Pathol., September 1, 2006; 169(3): 987 - 998. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Yamaguchi, N. Aihara, T. Kojima, and K. Kasai RANKL Increase in Compressed Periodontal Ligament Cells from Root Resorption Journal of Dental Research, August 1, 2006; 85(8): 751 - 756. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Liu, K. Igarashi, H. Kanzaki, M. Chiba, H. Shinoda, and H. Mitani Clodronate Inhibits PGE2 Production in Compressed Periodontal Ligament Cells Journal of Dental Research, August 1, 2006; 85(8): 757 - 760. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Aharon and Z. Bar-Shavit Involvement of Aquaporin 9 in Osteoclast Differentiation J. Biol. Chem., July 14, 2006; 281(28): 19305 - 19309. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Tsukiyama, Y. Yamada, C. Yamada, N. Harada, Y. Kawasaki, M. Ogura, K. Bessho, M. Li, N. Amizuka, M. Sato, et al. Gastric Inhibitory Polypeptide as an Endogenous Factor Promoting New Bone Formation after Food Ingestion Mol. Endocrinol., July 1, 2006; 20(7): 1644 - 1651. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Yamamoto, N. Udagawa, S. Matsuura, Y. Nakamichi, H. Horiuchi, A. Hosoya, M. Nakamura, H. Ozawa, K. Takaoka, J. M. Penninger, et al. Osteoblasts Provide a Suitable Microenvironment for the Action of Receptor Activator of Nuclear Factor-{kappa}B Ligand Endocrinology, July 1, 2006; 147(7): 3366 - 3374. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. L. Fisher, R. J. Thomas-Mudge, J. Elliott, D. K. Hards, N. A. Sims, J. Slavin, T. J. Martin, and M. T. Gillespie Osteoprotegerin overexpression by breast cancer cells enhances orthotopic and osseous tumor growth and contrasts with that delivered therapeutically. Cancer Res., April 1, 2006; 66(7): 3620 - 3628. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Fuller, B. Kirstein, and T. J. Chambers Murine Osteoclast Formation and Function: Differential Regulation by Humoral Agents Endocrinology, April 1, 2006; 147(4): 1979 - 1985. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. J. Spencer, J. C. Utting, S. L. Etheridge, T. R. Arnett, and P. G. Genever Wnt signalling in osteoblasts regulates expression of the receptor activator of NF{kappa}B ligand and inhibits osteoclastogenesis in vitro J. Cell Sci., April 1, 2006; 119(7): 1283 - 1296. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Lee, K. Kim, J. H. Kim, H. M. Jin, H. K. Choi, S.-H. Lee, H. Kook, K. K. Kim, Y. Yokota, S. Y. Lee, et al. Id helix-loop-helix proteins negatively regulate TRANCE-mediated osteoclast differentiation Blood, April 1, 2006; 107(7): 2686 - 2693. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 U. Kornak, A. Ostertag, S. Branger, O. Benichou, and M.-C. de Vernejoul Polymorphisms in the CLCN7 Gene Modulate Bone Density in Postmenopausal Women and in Patients with Autosomal Dominant Osteopetrosis Type II J. Clin. Endocrinol. Metab., March 1, 2006; 91(3): 995 - 1000. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
X. Wang, H.-Y. Kua, Y. Hu, K. Guo, Q. Zeng, Q. Wu, H.-H. Ng, G. Karsenty, B. de Crombrugghe, J. Yeh, et al. p53 functions as a negative regulator of osteoblastogenesis, osteoblast-dependent osteoclastogenesis, and bone remodeling J. Cell Biol., January 3, 2006; 172(1): 115 - 125. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
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|
|
|
|
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W. Liu, S. Wang, S. Wei, L. Sun, and X. Feng Receptor Activator of NF-{kappa}B (RANK) Cytoplasmic Motif, 369PFQEP373, Plays a Predominant Role in Osteoclast Survival in Part by Activating Akt/PKB and Its Downstream Effector AFX/FOXO4 J. Biol. Chem., December 30, 2005; 280(52): 43064 - 43072. [Abstract] [Full Text] [PDF]
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L. A. Schneeweis, D. Willard, and M. E. Milla Functional Dissection of Osteoprotegerin and Its Interaction with Receptor Activator of NF-{kappa}B Ligand J. Biol. Chem., December 16, 2005; 280(50): 41155 - 41164. [Abstract] [Full Text] [PDF]
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J. Kohrle, F. Jakob, B. Contempre, and J. E. Dumont Selenium, the Thyroid, and the Endocrine System Endocr. Rev., December 1, 2005; 26(7): 944 - 984. [Abstract] [Full Text] [PDF]
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M. S. Bendre, A. G. Margulies, B. Walser, N. S. Akel, S. Bhattacharrya, R. A. Skinner, F. Swain, V. Ramani, K. S. Mohammad, L. L. Wessner, et al. Tumor-Derived Interleukin-8 Stimulates Osteolysis Independent of the Receptor Activator of Nuclear Factor-{kappa}B Ligand Pathway Cancer Res., December 1, 2005; 65(23): 11001 - 11009. [Abstract] [Full Text] [PDF]
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I. Take, Y. Kobayashi, Y. Yamamoto, H. Tsuboi, T. Ochi, S. Uematsu, N. Okafuji, S. Kurihara, N. Udagawa, and N. Takahashi Prostaglandin E2 Strongly Inhibits Human Osteoclast Formation Endocrinology, December 1, 2005; 146(12): 5204 - 5214. [Abstract] [Full Text] [PDF]
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K. Kim, J. H. Kim, J. Lee, H.-M. Jin, S.-H. Lee, D. E. Fisher, H. Kook, K. K. Kim, Y. Choi, and N. Kim Nuclear Factor of Activated T Cells c1 Induces Osteoclast-associated Receptor Gene Expression during Tumor Necrosis Factor-related Activation-induced Cytokine-mediated Osteoclastogenesis J. Biol. Chem., October 21, 2005; 280(42): 35209 - 35216. [Abstract] [Full Text] [PDF]
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 S. Bord, D. C. Ireland, P. Moffatt, G. P. Thomas, and J. E. Compston Characterization of Osteocrin Expression in Human Bone J. Histochem. Cytochem., October 1, 2005; 53(10): 1181 - 1187. [Abstract] [Full Text] [PDF]
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S. Koga, K. Yogo, K. Yoshikawa, H. Samori, M. Goto, T. Uchida, N. Ishida, and T. Takeya Physical and Functional Association of c-Src and Adhesion and Degranulation Promoting Adaptor Protein (ADAP) in Osteoclastogenesis in Vitro J. Biol. Chem., September 9, 2005; 280(36): 31564 - 31571. [Abstract] [Full Text] [PDF]
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N. Kim, Y. Kadono, M. Takami, J. Lee, S.-H. Lee, F. Okada, J. H. Kim, T. Kobayashi, P. R. Odgren, H. Nakano, et al. Osteoclast differentiation independent of the TRANCE-RANK-TRAF6 axis J. Exp. Med., September 6, 2005; 202(5): 589 - 595. [Abstract] [Full Text] [PDF]
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S. Nagpal, S. Na, and R. Rathnachalam Noncalcemic Actions of Vitamin D Receptor Ligands Endocr. Rev., August 1, 2005; 26(5): 662 - 687. [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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N. K. Lee, Y. G. Choi, J. Y. Baik, S. Y. Han, D.-w. Jeong, Y. S. Bae, N. Kim, and S. Y. Lee A crucial role for reactive oxygen species in RANKL-induced osteoclast differentiation Blood, August 1, 2005; 106(3): 852 - 859. [Abstract] [Full Text] [PDF]
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Y. Kobayashi, I. Take, T. Yamashita, T. Mizoguchi, T. Ninomiya, T. Hattori, S. Kurihara, H. Ozawa, N. Udagawa, and N. Takahashi Prostaglandin E2 Receptors EP2 and EP4 Are Down-regulated during Differentiation of Mouse Osteoclasts from Their Precursors J. Biol. Chem., June 24, 2005; 280(25): 24035 - 24042. [Abstract] [Full Text] [PDF]
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M. G. Ruocco, S. Maeda, J. M. Park, T. Lawrence, L.-C. Hsu, Y. Cao, G. Schett, E. F. Wagner, and M. Karin I{kappa}B kinase (IKK){beta}, but not IKK{alpha}, is a critical mediator of osteoclast survival and is required for inflammation-induced bone loss J. Exp. Med., May 16, 2005; 201(10): 1677 - 1687. [Abstract] [Full Text] [PDF]
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Y. Kobayashi, T. Mizoguchi, I. Take, S. Kurihara, N. Udagawa, and N. Takahashi Prostaglandin E2 Enhances Osteoclastic Differentiation of Precursor Cells through Protein Kinase A-dependent Phosphorylation of TAK1 J. Biol. Chem., March 25, 2005; 280(12): 11395 - 11403. [Abstract] [Full Text] [PDF]
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S. D. Yogesha, S. M. Khapli, and M. R. Wani Interleukin-3 and Granulocyte-Macrophage Colony-stimulating Factor Inhibits Tumor Necrosis Factor (TNF)-{alpha}-induced Osteoclast Differentiation by Down-regulation of Expression of TNF Receptors 1 and 2 J. Biol. Chem., March 25, 2005; 280(12): 11759 - 11769. [Abstract] [Full Text] [PDF]
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T. M. Murray, L. G. Rao, P. Divieti, and F. R. Bringhurst Parathyroid Hormone Secretion and Action: Evidence for Discrete Receptors for the Carboxyl-Terminal Region and Related Biological Actions of Carboxyl- Terminal Ligands Endocr. Rev., February 1, 2005; 26(1): 78 - 113. [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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W. Gianni, A. Ricci, P. Gazzaniga, M. Brama, M. Pietropaolo, S. Votano, F. Patane, A. M. Agliano, G. Spera, V. Marigliano, et al. Raloxifene Modulates Interleukin-6 and Tumor Necrosis Factor-{alpha} Synthesis in Vivo: Results from a Pilot Clinical Study J. Clin. Endocrinol. Metab., December 1, 2004; 89(12): 6097 - 6099. [Abstract] [Full Text] [PDF]
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M. Matsumoto, M. Kogawa, S. Wada, H. Takayanagi, M. Tsujimoto, S. Katayama, K. Hisatake, and Y. Nogi Essential Role of p38 Mitogen-activated Protein Kinase in Cathepsin K Gene Expression during Osteoclastogenesis through Association of NFATc1 and PU.1 J. Biol. Chem., October 29, 2004; 279(44): 45969 - 45979. [Abstract] [Full Text] [PDF]
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T. Kukita, N. Wada, A. Kukita, T. Kakimoto, F. Sandra, K. Toh, K. Nagata, T. Iijima, M. Horiuchi, H. Matsusaki, et al. RANKL-induced DC-STAMP Is Essential for Osteoclastogenesis J. Exp. Med., October 4, 2004; 200(7): 941 - 946. [Abstract] [Full Text] [PDF]
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N. Sato, N. Takahashi, K. Suda, M. Nakamura, M. Yamaki, T. Ninomiya, Y. Kobayashi, H. Takada, K. Shibata, M. Yamamoto, et al. MyD88 But Not TRIF Is Essential for Osteoclastogenesis Induced by Lipopolysaccharide, Diacyl Lipopeptide, and IL-1{alpha} J. Exp. Med., September 7, 2004; 200(5): 601 - 611. [Abstract] [Full Text] [PDF]
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D. Kamei, K. Yamakawa, Y. Takegoshi, M. Mikami-Nakanishi, Y. Nakatani, S. Oh-ishi, H. Yasui, Y. Azuma, N. Hirasawa, K. Ohuchi, et al. Reduced Pain Hypersensitivity and Inflammation in Mice Lacking Microsomal Prostaglandin E Synthase-1 J. Biol. Chem., August 6, 2004; 279(32): 33684 - 33695. [Abstract] [Full Text] [PDF]
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T. M. Doherty, L. A. Fitzpatrick, D. Inoue, J.-H. Qiao, M. C. Fishbein, R. C. Detrano, P. K. Shah, and T. B. Rajavashisth Molecular, Endocrine, and Genetic Mechanisms of Arterial Calcification Endocr. Rev., August 1, 2004; 25(4): 629 - 672. [Abstract] [Full Text] [PDF]
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Y. Okamatsu, D. Kim, R. Battaglino, H. Sasaki, U. Spate, and P. Stashenko MIP-1 gamma promotes receptor-activator-of-NF-kappa-B-ligand-induced osteoclast formation and survival. J. Immunol., August 1, 2004; 173(3): 2084 - 2090. [Abstract] [Full Text] [PDF]
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M. Bastepe, A. Raas-Rothschild, J. Silver, I. Weissman, S. Wientroub, H. Juppner, and D. Gillis A Form of Jansen's Metaphyseal Chondrodysplasia with Limited Metabolic and Skeletal Abnormalities Is Caused by a Novel Activating Parathyroid Hormone (PTH)/PTH-Related Peptide Receptor Mutation J. Clin. Endocrinol. Metab., July 1, 2004; 89(7): 3595 - 3600. [Abstract] [Full Text] [PDF]
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 S. Ishikawa, N. Arase, T. Suenaga, Y. Saita, M. Noda, T. Kuriyama, H. Arase, and T. Saito Involvement of FcR{gamma} in signal transduction of osteoclast-associated receptor (OSCAR) Int. Immunol., July 1, 2004; 16(7): 1019 - 1025. [Abstract] [Full Text] [PDF]
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D. Vanderschueren, L. Vandenput, S. Boonen, M. K. Lindberg, R. Bouillon, and C. Ohlsson Androgens and Bone Endocr. Rev., June 1, 2004; 25(3): 389 - 425. [Abstract] [Full Text] [PDF]
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K. Saito, N. Ohara, H. Hotokezaka, S. Fukumoto, K. Yuasa, M. Naito, T. Fujiwara, and K. Nakayama Infection-induced Up-regulation of the Costimulatory Molecule 4-1BB in Osteoblastic Cells and Its Inhibitory Effect on M-CSF/RANKL-induced in Vitro Osteoclastogenesis J. Biol. Chem., April 2, 2004; 279(14): 13555 - 13563. [Abstract] [Full Text] [PDF]
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J. L. Roccisana, N. Kawanabe, H. Kajiya, M. Koide, G. D. Roodman, and S. V. Reddy Functional Role for Heat Shock Factors in the Transcriptional Regulation of Human RANK Ligand Gene Expression in Stromal/Osteoblast Cells J. Biol. Chem., March 12, 2004; 279(11): 10500 - 10507. [Abstract] [Full Text] [PDF]
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N. Okahashi, H. Inaba, I. Nakagawa, T. Yamamura, M. Kuboniwa, K. Nakayama, S. Hamada, and A. Amano Porphyromonas gingivalis Induces Receptor Activator of NF-{kappa}B Ligand Expression in Osteoblasts through the Activator Protein 1 Pathway Infect. Immun., March 1, 2004; 72(3): 1706 - 1714. [Abstract] [Full Text] [PDF]
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H.-I. Shin, P. Divieti, N. A. Sims, T. Kobayashi, D. Miao, A. C. Karaplis, R. Baron, R. Bringhurst, and H. M. Kronenberg gp130-Mediated Signaling Is Necessary for Normal Osteoblastic Function in Vivo and in Vitro Endocrinology, March 1, 2004; 145(3): 1376 - 1385. [Abstract] [Full Text] [PDF]
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A. Matsunuma, T. Kawane, T. Maeda, S. Hamada, and N. Horiuchi Leptin Corrects Increased Gene Expression of Renal 25-Hydroxyvitamin D3-1{alpha}-Hydroxylase and -24-Hydroxylase in Leptin-Deficient, ob/ob Mice Endocrinology, March 1, 2004; 145(3): 1367 - 1375. [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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S. Niida, M. Kawahara, Y. Ishizuka, Y. Ikeda, T. Kondo, T. Hibi, Y. Suzuki, K. Ikeda, and N. Taniguchi {gamma}-Glutamyltranspeptidase Stimulates Receptor Activator of Nuclear Factor-{kappa}B Ligand Expression Independent of Its Enzymatic Activity and Serves as a Pathological Bone-resorbing Factor J. Biol. Chem., February 13, 2004; 279(7): 5752 - 5756. [Abstract] [Full Text] [PDF]
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 E. Tian, F. Zhan, R. Walker, E. Rasmussen, Y. Ma, B. Barlogie, and J. D. Shaughnessy Jr. The Role of the Wnt-Signaling Antagonist DKK1 in the Development of Osteolytic Lesions in Multiple Myeloma N. Engl. J. Med., December 25, 2003; 349(26): 2483 - 2494. [Abstract] [Full Text] [PDF]
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D.-H. Chung, M. B. Humphrey, M. C. Nakamura, D. G. Ginzinger, W. E. Seaman, and M. R. Daws CMRF-35-Like Molecule-1, a Novel Mouse Myeloid Receptor, Can Inhibit Osteoclast Formation J. Immunol., December 15, 2003; 171(12): 6541 - 6548. [Abstract] [Full Text] [PDF]
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G. Thomas, P. Moffatt, P. Salois, M.-H. Gaumond, R. Gingras, E. Godin, D. Miao, D. Goltzman, and C. Lanctot Osteocrin, a Novel Bone-specific Secreted Protein That Modulates the Osteoblast Phenotype J. Biol. Chem., December 12, 2003; 278(50): 50563 - 50571. [Abstract] [Full Text] [PDF]
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M. Nakamura, N. Udagawa, S. Matsuura, M. Mogi, H. Nakamura, H. Horiuchi, N. Saito, B. Y. Hiraoka, Y. Kobayashi, K. Takaoka, et al. Osteoprotegerin Regulates Bone Formation through a Coupling Mechanism with Bone Resorption Endocrinology, December 1, 2003; 144(12): 5441 - 5449. [Abstract] [Full Text] [PDF]
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A. Takuma, T. Kaneda, T. Sato, S. Ninomiya, M. Kumegawa, and Y. Hakeda Dexamethasone Enhances Osteoclast Formation Synergistically with Transforming Growth Factor-{beta} by Stimulating the Priming of Osteoclast Progenitors for Differentiation into Osteoclasts J. Biol. Chem., November 7, 2003; 278(45): 44667 - 44674. [Abstract] [Full Text] [PDF]
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 E. Seeman Invited Review: Pathogenesis of osteoporosis J Appl Physiol, November 1, 2003; 95(5): 2142 - 2151. [Abstract] [Full Text] [PDF]
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X. Li, N. Udagawa, M. Takami, N. Sato, Y. Kobayashi, and N. Takahashi p38 Mitogen-Activated Protein Kinase Is Crucially Involved in Osteoclast Differentiation But Not in Cytokine Production, Phagocytosis, or Dendritic Cell Differentiation of Bone Marrow Macrophages Endocrinology, November 1, 2003; 144(11): 4999 - 5005. [Abstract] [Full Text] [PDF]
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A. Sakurai, N. Okahashi, I. Nakagawa, S. Kawabata, A. Amano, T. Ooshima, and S. Hamada Streptococcus pyogenes Infection Induces Septic Arthritis with Increased Production of the Receptor Activator of the NF-{kappa}B Ligand Infect. Immun., October 1, 2003; 71(10): 6019 - 6026. [Abstract] [Full Text] [PDF]
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A. N. Farrugia, G. J. Atkins, L. B. To, B. Pan, N. Horvath, P. Kostakis, D. M. Findlay, P. Bardy, and A. C. W. Zannettino Receptor Activator of Nuclear Factor-{kappa}B Ligand Expression by Human Myeloma Cells Mediates Osteoclast Formation in Vitro and Correlates with Bone Destruction in Vivo Cancer Res., September 1, 2003; 63(17): 5438 - 5445. [Abstract] [Full Text] [PDF]
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R. Chiusaroli, A. Maier, M. C. Knight, M. Byrne, L. M. Calvi, R. Baron, S. M. Krane, and E. Schipani Collagenase Cleavage of Type I Collagen Is Essential for Both Basal and Parathyroid Hormone (PTH)/PTH-Related Peptide Receptor-Induced Osteoclast Activation and Has Differential Effects on Discrete Bone Compartments Endocrinology, September 1, 2003; 144(9): 4106 - 4116. [Abstract] [Full Text] [PDF]
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