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Research Institute of Life Science, Snow Brand Milk Products Co., Ltd., 519 Ishibashi-machi, Shimotsuga-gun, Tochigi, 329–0512, Japan
Address all correspondence and requests for reprints to: Hisataka Yasuda, Research Institute of Life Science, Snow Brand Milk Products Co., Ltd., 519 Ishibashi-machi, Shimotsuga-gun, Tochigi, 329–0512, Japan. E-mail: fvbd7042{at}mb.infoweb.or.jp
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Osteoclast-like multinucleated cells can be formed in vitro by culturing bone marrow cells or by coculturing spleen cells with osteoblasts or bone marrow-derived stromal cells in the presence of such stimulators of bone resorption as interleukin-6 (IL-6), PTH, 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] (3, 4, 5, 6). Osteoblasts or stromal cells are essential for in vitro osteoclastogenesis and involved in osteoclast differentiation by producing soluble factors and by signaling to osteoclast progenitors through cell-to-cell interaction (4, 5, 6). Among soluble factors produced by stromal cells, macrophage-colony stimulating factor (M-CSF) is the most important and appears to be necessary for both proliferation and differentiation of osteoclast progenitors (7, 8, 9, 10). On the other hand, it is proposed that "osteoclast differentiation factor" (3, 4) or "stromal osteoclast-forming activity" (11), which is a hypothetical factor expressed on stromal cells, regulates osteoclastogenesis by interacting with osteoclast progenitors, although little is known about the cell-to-cell signaling. For the understanding of the mechanism by which hematopoietic precursors differentiate into osteoclasts, identification of factors involved in the process is essential.
We previously reported the purification of osteoclastogenesis inhibitory factor, OCIF, which inhibits osteoclast development, from the conditioned medium of human embryonic fibroblasts, IMR-90 (12). OCIF is a heparin-binding basic glycoprotein and has been isolated as a monomer with an apparent molecular weight (Mr) of 60K and a disulfide-linked homodimer with a Mr of 120K. OCIF specifically inhibits in vitro osteoclastogenesis elicited through three distinct signaling pathways stimulated by 1,25-(OH)2D3, PTH, and IL-11, respectively.
In the present study, we report the isolation of complementary DNA (cDNA) of human OCIF, a new soluble member of the tumor necrosis factor receptor (TNFR) family, and the biological activity of recombinant human OCIF (rhOCIF) in vivo. We propose that OCIF inhibits in vitro osteoclastogenesis by interrupting cell-to-cell signaling between stromal cells and osteoclast progenitors.
During the preparation of this manuscript, Simonet et al. (13) reported the cloning of osteoprotegerin (OPG), a secreted protein involved in the regulation of bone density. OPG cDNA has been isolated by sequence homology as a possible novel member of the TNFR family in a fetal rat intestine expressed sequence tag (EST) cDNA project. Administration of recombinant murine OPG fused to human immunoglobulin IgG1 Fc domain (murine OPG-Fc) to animals results in osteopetrosis, coincident with a decrease of osteoclast differentiation in later stages. Comparison of the amino-acid sequences of OCIF and OPG revealed identity between the two proteins. We refer OCIF to OPG/OCIF in this manuscript.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-MEM were from
GIBCO-BRL (Rockville, MD). IODO-GEN, disuccinimidyl suberate (DSS) and
disuccinimidyl tartarate (DST) were from PIERCE (Rockford, IL).
Paraformaldehyde was from TAAB Laboratories Equipment (Berks, UK).
125I-salmon calcitonin was from Amersham International
(Little Chalfont, Buckinghamshire, UK). Salmon calcitonin was from
BACHEM California (Torrance, CA). Triton X-100, PMSF, leupeptine,
antipain, pepstain A, and aprotinin were from Sigma Chemical Co. (St.
Louis, MO). IMR-90 cells and CHOdhfr- cells were from American Type
Culture Collection (Rockville, MD). ST2 cells and MC3T3-E1 cells were
from RIKEN CELL BANK (Ibaraki, Japan). All other chemicals used in this
study were of analytical grade.
cDNA cloning
Based on the internal amino acid sequences of OCIF (12), two
primer pools were synthesized: primer no. 2F
(5'-CARGARCARACNTTYCARYT-3', [IUB codes)), a sense-strand primer
encoding amino-acid sequence, QEQTFQL, and primer no. 3R
(5'-YTTRTACATNGTRAANSWRT-3'), an antisense-strand primer encoding
amino-acid sequence, HSFTMYK. First-strand cDNA was generated with
oligo (dT) primer and poly(A)+RNA from IMR-90 cells using
SuperScript Preamplification System. A 397-bp product was obtained by
PCR (PCR) with Taq polymerase using the cDNA as a template.
The reactions were 95 C for 30 sec, 50 C for 30 sec, and 70 C for 2 min
for 30 cycles. The 397-bp product was subcloned and sequenced using
AmpliTaq DyeDeoxy Terminator Cycle Sequencing on an ABI 373A sequencer
(Perkin-Elmer). A cDNA library in 
ZAP Express constructed with
poly(A)+ RNA from IMR-90 cells was screened with the
32P-labeled 397-bp product. The 1.6-kb insert of OIF10
was sequenced as described above.
Northern blot analysis
Adult and fetal human multitissue Northern blots contained
approximately 2 µg poly(A)+ RNA per lane. Other blots
contained 20 µg of total RNA per lane. RNA extraction and
hybridization were done as described (14). Glyceraldehyde-3-phosphate
dehydrogenase (GAPDH) messenger RNA (mRNA) or ß-actin mRNA was used
as an internal control.
Preparation of rhOPG/OCIF
The full-length human OPG/OCIF cDNA was inserted into the
expression vector pcDL-SR296 (15) to construct pSROPG/OCIF. An
expression unit of mouse dihydrofolate reductase (DHFR) gene (16) was
inserted into pBluescript to construct pBdhfr. pSROPG/OCIF and
pBdhfr were cotransfected into CHOdhfr- cells by
electroporation using a gene pulser (Bio-Rad Laboratories, Hercules,
CA) set at 360 V and 960 µF. The transfected cells were selected with
methotrexate. rhOPG/OCIF was purified from conditioned media of cells
expressing high levels of OPG/OCIF as described (12) with modifications
(A. Tomoyasu et al., in preparation). All experiments were
performed using dimer rhOPG/OCIF (Mr 120K). The exception
is the chemical cross-linking analysis in which monomer rhOPG/OCIF
(Mr 60K) was used.
Osteoclast-like cell formation assays
Spleen cells (1 x 105 cells) prepared from
normal male ddY mice (6- to 15-week old) and ST2 cells (4 x
103 cells) were cocultured on a 96-well plate in -MEM
supplemented with 10% FCS for a week in the presence of 10
nM 1,25-(OH)2D3 and 100
nM dexamethasone and osteoclast-like cell formation was
evaluated by measuring tartrate-resistant acid phosphatase (TRAP)
activity as described (12). The cocultures were treated with 100 ng/ml
rhOPG/OCIF for a week or the indicated periods. To examine the effect
of OPG/OCIF on the osteoclast-like cell formation mediated by the fixed
ST2 cells, ST2 cells (2 x 104 cells) were cultured on
a 24-well plate in -MEM containing 10% FCS for 4 days in the
presence of 10 nM 1,25-(OH)2D3 and
100 nM dexamethasone. The
1,25-(OH)2D3-treated cells were incubated at 37
C for 1 h in the presence or absence of 100 ng/ml rhOPG/OCIF and
washed with PBS three times. The cells were then fixed in PBS
containing 1% paraformaldehyde for 8 min at room temperature and
washed with PBS six times. Mouse spleen cells (7 x
105 cells) were cultured for 6 days on the fixed cells in
-MEM containing 10% FCS in the presence of 10 nM
1,25-(OH)2D3, 100 nM dexamethasone,
and 25% conditioned medium of the
1,25-(OH)2D3-treated ST2 cells. The cells were
subjected to the binding assay using 125I-salmon calcitonin
or were fixed and stained for TRAP as described (12). For the binding
assay using 125I-calcitonin, the cells were incubated with
0.25 nM 125I-calcitonin in the presence or
absence of 100 nM unlabeled calcitonin for 1 h at 37 C
in 200 µl of binding medium [-MEM containing 20 mM
HEPES (pH 7.3), and 0.1% BSA]. The cells were washed with PBS
containing 0.1% BSA three times and lysed in 500 µl of 0.1
N NaOH. The radioactivity was measured using a 
-counter
(AUTO-GAMMA 5650, Packard Instrument Co., Meriden, CT).
Animal treatment
ddY mice were purchased from Japan SLC, Inc. (Shizuoka, Japan).
Sprague Dawley rats were from Charles River Japan Inc. (Yokohama,
Japan). Male Sprague Dawley rats (5 weeks old) were injected iv with
rhOPG/OCIF (3 or 24 mg/kg·day) or with vehicle (PBS) for 2 weeks
(n = 4). On day 14, animals were anesthetized and the tibias and
femurs were removed. The bone mineral density (BMD) in the proximal
tibial metaphysis was measured by dual energy x-ray absorptiometry
(DCS-600, Aloka, Tokyo, Japan). The femurs were fixed in 10% neutral
buffered formalin, decalcified in formic acid, dehydrated, embedded in
paraffin, cut into 4–6 µm sections, and stained with
hematoxylin-eosin. Bone volume and active osteoclast numbers were
determined in five regions (0.73 x 0.95 mm) in the proximal area
between 0.3 and 2.5 mm from the growth plate in the distal femoral
metaphysis. Osteoclasts were identified microscopically based on
morphology and osteoclasts at the bone resorbing sites were considered
to be active. The numbers were expressed relative to bone
perimeter.
The animal studies were approved by the Animal Care and Use Committee of our institute and conducted in accordance with the NIH Guide for the Care and Use of Laboratory Animals.
Binding analyses using 125I-rhOPG/OCIF
Radioiodination of rhOPG/OCIF using IODO-GEN and Scatchard
analysis were performed as described (17). ST2 cells were cultured in
the presence or absence of 1,25-(OH)2D3 and
dexamethasone on 24-well plates as described in osteoclast-like cell
formation assays. The binding assay was performed by incubating the
cells with various concentrations of 125I-rhOPG/OCIF in the
presence or absence of 500 nM unlabeled rhOPG/OCIF for
1 h at 37 C in 200 µl of binding medium [-MEM containing 20
mM HEPES (pH 7.3), 0.2% BSA, and 0.02% sodium azide].
The cells were washed with PBS three times and lysed in 500 µl of 0.1
N NaOH. The radioactivity was determined as described
above. For chemical cross-linking, the
1,25-(OH)2D3-treated ST2 cells were incubated
with 0.33 nM 125I-monomer rhOPG/OCIF in the
presence or absence of 66 nM unlabeled rhOPG/OCIF, treated
with a mixture of 1 mM DSS and 1 mM DST on ice
for 1 h, and lysed on ice for 15 min in 1% Triton X-100
containing the following protease inhibitors: 2 mM PMSF, 2
mM EDTA, 100 µM leupeptine, 10
µM antipain, 10 µM pepstain A, and 0.2
TIU/ml aprotinin. The samples were electrophoresed on 10 to 20%
gradient sodium dodecyl sulfate polyacrylamide gel under reducing
conditions. The gel was dried and subjected to autoradiography.
Analyses of the inhibition of both biological activity of OPG/OCIF
and its binding to ST2 cells by anti-rhOPG/OCIF monoclonal antibodies
(mAbs)
Anti-rhOPG/OCIF mAbs were prepared and purified in our
laboratory. Details will be published elsewhere (K. Yano et
al., in preparation). To analyze the inhibition of both biological
activity of OPG/OCIF and its binding to ST2 cells by anti-rhOPG/OCIF
mAbs, 500 ng/ml anti-rhOPG/OCIF mAb (no. 1 or no. 18) or murine
immunogloblin G1 (mIgG) was preincubated with 10 ng/ml
125I-labeled or unlabeled rhOPG/OCIF for 1 h at 37 C.
The mixtures were subjected to the osteoclast-like cell formation assay
or to the binding to 1,25-(OH)2D3-treated ST2
cells.
Statistical analysis
Data were analyzed by ANOVA followed by Fisher’s protected
least significance difference. Statistical analysis was performed with
a software package (Statview J-4.5, Abacus Concepts, Berkeley, CA).
P < 0.05 was considered statistically significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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).
OPG/OCIF is a novel member of the TNFR family including TNFR 1 (18),
Fas (19), and the poxvirus gene product, T2 (PV-T2) (20). When the
amino-acid sequence of the C-terminal 204 residues of OPG/OCIF was
compared with the cytoplasmic domains of the members of the TNFR
family, a significant similarity was found with TNFR 1 and Fas in the
regions called "death domain (DD)" (21, 22). As aligned with
several DD proteins (23, 24), OPG/OCIF was found to contain two death
domain homologous regions (DDH1 and DDH2) that were present in tandem
(Fig. 1B). OPG/OCIF lacks apparent transmembrane (TM) domain and is
secreted into culture media.
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). The major band of 2.4-kb
represents a transcript encoding OPG/OCIF. The 4.2- and 6.5-kb
transcripts represent alternatively spliced forms containing all or a
portion of the second intron and do not encode OPG/OCIF containing a TM
domain (OPG/OCIF-TM). Attempts to clone OPG/OCIF-TM cDNA from tissues
failed. Sequence analysis of the human OPG/OCIF gene revealed that
there was no potential TM coding region in the third intron that
intervenes between the cysteine-rich domains and DDHs (T. Morinaga
et al., in preparation). At present there is no evidence
suggesting the presence of a membrane-bound OPG/OCIF. OPG/OCIF gene was
expressed in every tissue of human adult and fetus with a exception of
PBL (Fig. 2B). The expression was high especially in thyroid, kidney,
heart, spinal cord, and liver, although no transcripts were detected in
liver in the previous report by Simonet et al. (13). There
are two major transcripts in such tissues as brain, placenta, spleen,
and prostate. The two transcripts are probably generated by the
alternative use of two major transcription initiation sites in human
OPG/OCIF gene (T. Morinaga et al., in preparation).
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). In addition, OPG/OCIF mRNA levels in
ST2 cells and mouse osteoblastic MC3T3-E1 cells increased in response
to calcium ions, although the increase of the mRNA in ST2 cells was not
so obvious (Fig. 2C).
rhOPG/OCIF inhibits osteoclastogenesis in vitro
The OPG/OCIF cDNA was expressed in mammalian cells, and the
biological activity of rhOPG/OCIF was examined in an in
vitro osteoclast-like cell formation assay (3, 4, 6, 26) as
evaluated by TRAP activity (data not shown) and calcitonin binding, a
combination of features unique to osteoclastic cells (1, 3). rhOPG/OCIF
as well as native OCIF (12) inhibited in a dose-dependent manner
osteoclast-like cell formation from mouse spleen cells cocultured with
ST2 cells in the presence of 1,25-(OH)2D3 (Fig. 3A). Because ST2 cells express OPG/OCIF
gene in the absence of 1,25-(OH)2D3 (Fig. 2C),
we examined whether the gene expression in ST2 cells contradicts the
observations that the cells support osteoclastogenesis. The OPG/OCIF
gene expression was suppressed by 1,25-(OH)2D3
in both the culture of ST2 cells and the cocultures in which
osteoclast-like cells were formed (Fig. 3B).
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, A and B).
The animals received the higher dose exhibited a marked increase of
trabecular bones in the marrow cavities of the distal metaphysis of the
femur (Fig. 4A) with remarkable increases in BMD (1.5-fold) and bone
volume (1.8-fold) (Fig. 4B). No changes were observed in the growth
plate and the diaphysis in the femur. The treated animals exhibited
neither histopathological abnormalities in 38 tissues including those
expressing high level of OPG/OCIF mRNA nor significant changes in the
number of leukocytes, erythrocytes, reticulocytes, or platelets. There
were no abnormalities in serum and urine chemical parameters.
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, OPG/OCIF specifically bound to
1,25-(OH)2D3-treated ST2 cells but not to
untreated ST2 cells. Scatchard plot analysis revealed the presence of a
single class of OPG/OCIF-binding sites (OBS) on the
1,25-(OH)2D3-treated ST2 cells with high
affinity (an equilibrium dissociation constant,
Kd = 289 pM) and at
8.5 x 104 binding sites/cell (Fig. 5, B and C). We
next investigated the relationship between the appearance of OBS and
the OPG/OCIF activity. Figure 6A shows
that OBS on ST2 cells increased in a time-dependent manner and reached
at a maximum on day 4 in the presence of
1,25-(OH)2D3. OPG/OCIF effectively inhibited
osteoclast development when added to the cocultures for 2 days: days 3
and 4 (Fig. 6B).
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, a mAb (no.1)
neutralized the OPG/OCIF activity. The mAb (no.1) also completely
blocked the binding of 125I-rhOPG/OCIF to the
1,25-(OH)2D3-treated ST2 cells. In contrast,
another mAb (no. 18), which has the affinity for OPG/OCIF comparable to
that of the no. 1-mAb, neither neutralized the activity nor blocked the
binding. To further elucidate the mechanism by which OPG/OCIF inhibits
osteoclastogenesis, we investigated whether titration of OBS with
rhOPG/OCIF abolished the osteoclast-like cell formation. The
1,25-(OH)2D3-treated ST2 cells were fixed with
paraformaldehyde, and then spleen cells were cultured on the fixed
cells in the presence of both 1,25-(OH)2D3 and
conditioned medium of 1,25-(OH)2D3-treated ST2
cells. As shown in Table 1, the fixed
cells induced the formation of osteoclast-like cells, evaluated by TRAP
staining and the binding of 125I-calcitonin. In contrast,
when the 1,25-(OH)2D3-treated ST2 cells were
incubated with rhOPG/OCIF before fixation, no osteoclast-like cells
were formed. When the similar experiments were performed using
1,25-(OH)2D3-untreated ST2 cells, no
osteoclast-like cells were formed under the same conditions. To
characterize OBS, 125I-monomer rhOPG/OCIF (Mr
60K) was chemically cross-linked to the
1,25-(OH)2D3-treated ST2 cells, and the
products were analyzed by electrophoresis. We found two major
cross-linked bands of Mr 100K and 180K, representing
OPG/OCIF binding protein(s) (OBP) of Mr 40K and 120K,
respectively (Fig. 8).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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nor lymphotoxin (LT) (our unpublished data),
suggesting that OPG/OCIF does not interact with TNF nor LT.
Analysis of the domain-deletion mutants revealed that cystein-rich
domains but not DDH regions are essential for the biological activity
in vitro (K. Yamaguchi, Ref.29), as reported by Shimonet
et al. (13). Because the cystein-rich domains of the TNFR
family members are considered to be the ligand-binding domain, these
domains of OPG/OCIF, which are essential for the inhibition of
osteoclastogenesis, may bind to a TNF-like ligand. OPG/OCIF is the
first example of two DDHs in a single polypeptide. The tandemly
presented DDHs are probably produced by a duplication. Whether the DDHs
are involved in interaction with other proteins or cell death
signaling, however, remains to be elucidated. OPG/OCIF gene is expressed in ubiquitous tissues except PBL; however, the physiological significance remains to be determined. Because OPG/OCIF is a secreted protein and the action of exogenous OPG/OCIF is systemic and specific to bone tissues, endogenous OPG/OCIF may act only on bone tissues in an endocrine fashion and does not necessarily play other specific roles in nonosseous tissues. It should be noted that thyroid, which expresses abundant OPG/OCIF mRNA, produces calcitonin that regulates the concentration of calcium ions in serum by suppressing born resorption. rhOPG/OCIF inhibited an osteoclast-like cell formation in the cocultures of ST2 cells and spleen cells, as native OCIF did (12). It is noteworthy that OPG/OCIF expression in ST2 cells is suppressed in the culture conditions that stimulate oseoclastogenesis. The results imply the possible role of OPG/OCIF expressed by stromal cells as a local factor. Regulation of OPG/OCIF gene expression by 1,25-(OH)2D3 and calcium ions raise the possibility that osteoclastogenesis is regulated by OPG/OCIF in response to stimulators of bone resorption and calcium ions released at bone-resorbing sites.
Administration of the authentic rhOPG/OCIF resulted in the increase of BMD and bone volume in normal rats with a decrease of active osteoclast number. rhOPG/OCIF also blocked the bone loss in ovariectomized rats (data not shown). rhOPG/OCIF specifically acted on the bone tissues as a systemic factor and caused the excess accumulation of newly synthesized bone by arresting osteoclast maturation. These data confirmed the report by Shimonet et al. (13) in which administration of recombinant murine OPG-Fc to animals results in osteopetrosis. Our study using the authentic rhOPG/OCIF extends the previous study using the Fc-fusion protein or transgenic mice (13).
The binding study revealed the presence of a single class of OBS on 1,25-(OH)2D3-treated ST2 cells with high affinity (Kd = 289 pM). The Kd value is comparable to the concentrations at which OPG/OCIF exerts its activity in vitro (1 to 40 ng/ml, equivalent to 8.3 to 333 pM) (12). Several lines of evidence suggest a close relationship between the appearance of OBS on ST2 cells and the OPG/OCIF activity. 1) OBS on ST2 cells increased in a time-dependent manner and reached at a maximum on day 4 in the presence of 1,25-(OH)2D3. 2) TRAP-positive mononuclear cells (preosteoclasts) and multinucleated cells (osteoclasts) are developed from the cocultures on day 3 and day 5, respectively (6, 26), coinciding with the increase of OBS. 3) OPG/OCIF effectively inhibited osteoclast development when added to the cocultures for 2 days, days 3 and 4. 4) The neutralizing mAb blocked the binding of OPG/OCIF to OBS. In addition to the supporting evidence, the titration of OBS with rhOPG/OCIF abolished the osteoclast-like cell formation in the culture of spleen cells on the fixed ST2 cells, suggesting that OBS is involved in cell-to-cell signaling between ST2 cells and osteoclast progenitors and that OPG/OCIF inhibits osteoclastogenesis by interrupting the signaling through the sites. These results also exclude the possibility that the activity of OPG/OCIF is due to titration of soluble factors.
The chemical cross-linking analysis suggests that OCIF/OPG binds to
OBP(s) of Mr 40K and 120K. The TNFR family members except
TNF receptors have a one ligand/one receptor binding principle (27, 30, 31). OBP is probably a new member of the TNF ligand family in which all
members except LT are type II membrane proteins (27, 31). Because
the TNF ligand family members are believed to be trimeric proteins
(30), the 120K protein may be the homo-trimer form of 40K OBP. We found
only 40K OBP in some chemical cross-linking experiments (data not
shown). The 120K protein may be high molecular mass cell surface
proteoglycans that do not cause direct biological effects. Taken
together, OBP would be a ligand involved in osteoclastogenesis and
identical to "osteoclast differentiation factor" (3, 4) or
"stromal osteoclast-forming activity" (11), which is a hypothetical
mediator involved in the cell-to-cell signaling to osteoclast
progenitors in osteoclastogenesis.
The present study suggests that OPG/OCIF plays an important role in bone remodeling and may be useful for the treatment of osteoporosis associated with increased osteoclast functions. The cloning of the OPG/OCIF cDNA opens new avenues of research into mechanisms of bone remodeling. Further characterization of OPG/OCIF and its binding protein (OBP) will provide insights into osteoclast biology.
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Acknowledgments |
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Footnotes |
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Received July 14, 1997.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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promoter: an efficient and versatile
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A. Rogers and R. Eastell Circulating Osteoprotegerin and Receptor Activator for Nuclear Factor {kappa}B Ligand: Clinical Utility in Metabolic Bone Disease Assessment J. Clin. Endocrinol. Metab., November 1, 2005; 90(11): 6323 - 6331. [Abstract] [Full Text] [PDF]
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 K. M. Roundy, G. Spangrude, J. J. Weis, and J. H. Weis Partial rescue of B cells in microphthalmic osteopetrotic marrow by loss of response to type I IFNs Int. Immunol., November 1, 2005; 17(11): 1495 - 1503. [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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 G A Clines and T A Guise Hypercalcaemia of malignancy and basic research on mechanisms responsible for osteolytic and osteoblastic metastasis to bone Endocr. Relat. Cancer, September 1, 2005; 12(3): 549 - 583. [Abstract] [Full Text] [PDF]
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 T. Cundy, J. Davidson, M. D. Rutland, C. Stewart, and A. M. DePaoli Recombinant Osteoprotegerin for Juvenile Paget's Disease N. Engl. J. Med., September 1, 2005; 353(9): 918 - 923. [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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 J.-h. Wang, M. Pazianas, W. D. Fraser, F. Harris, and J. B. Eastwood Acute renal failure and hypercalcaemia in a man from Guyana: what is the link? Nephrol. Dial. Transplant., July 1, 2005; 20(7): 1505 - 1508. [Full Text] [PDF]
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I. Avbersek-Luznik, B. P. Balon, I. Rus, and J. Marc Increased bone resorption in HD patients: is it caused by elevated RANKL synthesis? Nephrol. Dial. Transplant., March 1, 2005; 20(3): 566 - 570. [Abstract] [Full Text] [PDF]
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 V. P. Eswarakumar, M. C. Horowitz, R. Locklin, G. M. Morriss-Kay, and P. Lonai A gain-of-function mutation of Fgfr2c demonstrates the roles of this receptor variant in osteogenesis PNAS, August 24, 2004; 101(34): 12555 - 12560. [Abstract] [Full Text] [PDF]
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F.-S. Wang, C.-J. Wang, Y.-J. Chen, Y.-T. Huang, H.-C. Huang, P.-R. Chang, Y.-C. Sun, and K. D. Yang Nitric Oxide Donor Increases Osteoprotegerin Production and Osteoclastogenesis Inhibitory Activity in Bone Marrow Stromal Cells from Ovariectomized Rats Endocrinology, May 1, 2004; 145(5): 2148 - 2156. [Abstract] [Full Text] [PDF]
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 U. H. Lerner NEW MOLECULES IN THE TUMOR NECROSIS FACTOR LIGAND AND RECEPTOR SUPERFAMILIES WITH IMPORTANCE FOR PHYSIOLOGICAL AND PATHOLOGICAL BONE RESORPTION Critical Reviews in Oral Biology & Medicine, March 1, 2004; 15(2): 64 - 81. [Abstract] [Full Text] [PDF]
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K. H. Baek, W. Y. Lee, K. W. Oh, H. S. Kim, J. H. Han, M. I. Kang, B. Y. Cha, K. W. Lee, H. Y. Son, S. K. Kang, et al. Changes in the Serum Growth Factors and Osteoprotegerin after Bone Marrow Transplantation: Impact on Bone and Mineral Metabolism J. Clin. Endocrinol. Metab., March 1, 2004; 89(3): 1246 - 1254. [Abstract] [Full Text] [PDF]
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M. M. Tabb, A. Sun, C. Zhou, F. Grun, J. Errandi, K. Romero, H. Pham, S. Inoue, S. Mallick, M. Lin, et al. Vitamin K2 Regulation of Bone Homeostasis Is Mediated by the Steroid and Xenobiotic Receptor SXR J. Biol. Chem., November 7, 2003; 278(45): 43919 - 43927. [Abstract] [Full Text] [PDF]
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K. E. Naylor, A. Rogers, R. B. Fraser, V. Hall, R. Eastell, and A. Blumsohn Serum Osteoprotegerin as a Determinant of Bone Metabolism in a Longitudinal Study of Human Pregnancy and Lactation J. Clin. Endocrinol. Metab., November 1, 2003; 88(11): 5361 - 5365. [Abstract] [Full Text] [PDF]
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H. Enomoto, S. Shiojiri, K. Hoshi, T. Furuichi, R. Fukuyama, C. A. Yoshida, N. Kanatani, R. Nakamura, A. Mizuno, A. Zanma, et al. Induction of Osteoclast Differentiation by Runx2 through Receptor Activator of Nuclear Factor-{kappa}B Ligand (RANKL) and Osteoprotegerin Regulation and Partial Rescue of Osteoclastogenesis in Runx2-/- Mice by RANKL Transgene J. Biol. Chem., June 20, 2003; 278(26): 23971 - 23977. [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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G.E. Wise, Y. Ren, and S. Yao Regulation of Osteoprotegerin Gene Expression in Dental Follicle Cells Journal of Dental Research, April 1, 2003; 82(4): 298 - 302. [Abstract] [Full Text] [PDF]
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 T. Yamada, H. Yamazaki, T. Yamane, M. Yoshino, H. Okuyama, M. Tsuneto, T. Kurino, S.-I. Hayashi, and S. Sakano Regulation of osteoclast development by Notch signaling directed to osteoclast precursors and through stromal cells Blood, March 15, 2003; 101(6): 2227 - 2234. [Abstract] [Full Text] [PDF]
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B.-K. Choi, H. J. Lee, J. H. Kang, G. J. Jeong, C. K. Min, and Y.-J. Yoo Induction of Osteoclastogenesis and Matrix Metalloproteinase Expression by the Lipooligosaccharide of Treponema denticola Infect. Immun., January 1, 2003; 71(1): 226 - 233. [Abstract] [Full Text] [PDF]
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V. Hurgin, D. Novick, and M. Rubinstein The promoter of IL-18 binding protein: Activation by an IFN-gamma -induced complex of IFN regulatory factor 1 and CCAAT/enhancer binding protein beta PNAS, December 24, 2002; 99(26): 16957 - 16962. [Abstract] [Full Text] [PDF]
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 T N Crotti, M D Smith, H Weedon, M J Ahern, D M Findlay, M Kraan, P P Tak, and D R Haynes Receptor activator NF-{kappa}B ligand (RANKL) expression in synovial tissue from patients with rheumatoid arthritis, spondyloarthropathy, osteoarthritis, and from normal patients: semiquantitative and quantitative analysis Ann Rheum Dis, December 1, 2002; 61(12): 1047 - 1054. [Abstract] [Full Text] [PDF]
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D H. Jones, Y-Y Kong, and J M Penninger Role of RANKL and RANK in bone loss and arthritis Ann Rheum Dis, November 1, 2002; 61(90002): ii32 - 39. [Abstract] [Full Text] [PDF]
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B. Muller, G. Peri, A. Doni, A. P. Perruchoud, R. Landmann, F. Pasqualini, and A. Mantovani High circulating levels of the IL-1 type II decoy receptor in critically ill patients with sepsis: association of high decoy receptor levels with glucocorticoid administration J. Leukoc. Biol., October 1, 2002; 72(4): 643 - 649. [Abstract] [Full Text] [PDF]
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B. Arko, J. Prezelj, R. Komel, A. Kocijancic, P. Hudler, and J. Marc Sequence Variations in the Osteoprotegerin Gene Promoter in Patients with Postmenopausal Osteoporosis J. Clin. Endocrinol. Metab., September 1, 2002; 87(9): 4080 - 4084. [Abstract] [Full Text] [PDF]
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S. M. Krane Genetic Control of Bone Remodeling -- Insights from a Rare Disease N. Engl. J. Med., July 18, 2002; 347(3): 210 - 212. [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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M. Schoppet, K. T. Preissner, and L. C. Hofbauer RANK Ligand and Osteoprotegerin: Paracrine Regulators of Bone Metabolism and Vascular Function Arterioscler Thromb Vasc Biol, April 1, 2002; 22(4): 549 - 553. [Abstract] [Full Text] [PDF]
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S. Ito, K. Wakabayashi, O. Ubukata, S. Hayashi, F. Okada, and T. Hata Crystal Structure of the Extracellular Domain of Mouse RANK Ligand at 2.2-A Resolution J. Biol. Chem., February 15, 2002; 277(8): 6631 - 6636. [Abstract] [Full Text] [PDF]
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U Feige Osteoprotegerin Ann Rheum Dis, November 1, 2001; 60(90003): iii81 - 84. [Full Text] [PDF]
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P. A. Price, H. H. June, J. R. Buckley, and M. K. Williamson Osteoprotegerin Inhibits Artery Calcification Induced by Warfarin and by Vitamin D Arterioscler Thromb Vasc Biol, October 1, 2001; 21(10): 1610 - 1616. [Abstract] [Full Text] [PDF]
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 J. M. Brown, R. L. Vessella, P. J. Kostenuik, C. R. Dunstan, P. H. Lange, and E. Corey Serum Osteoprotegerin Levels Are Increased in Patients with Advanced Prostate Cancer Clin. Cancer Res., October 1, 2001; 7(10): 2977 - 2983. [Abstract] [Full Text] [PDF]
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Y. L. Ma, R. L. Cain, D. L. Halladay, X. Yang, Q. Zeng, R. R. Miles, S. Chandrasekhar, T. J. Martin, and J. E. Onyia Catabolic Effects of Continuous Human PTH (1-38) in Vivo Is Associated with Sustained Stimulation of RANKL and Inhibition of Osteoprotegerin and Gene-Associated Bone Formation Endocrinology, September 1, 2001; 142(9): 4047 - 4054. [Abstract] [Full Text] [PDF]
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T. Yamagishi, E. Otsuka, and H. Hagiwara Reciprocal Control of Expression of mRNAs for Osteoclast Differentiation Factor and OPG in Osteogenic Stromal Cells by Genistein: Evidence for the Involvement of Topoisomerase II in Osteoclastogenesis Endocrinology, August 1, 2001; 142(8): 3632 - 3637. [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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 D. Furuya, R. Kaneko, A. Yagihashi, T. Endoh, T. Yajima, D. Kobayashi, K. Yano, E. Tsuda, and N. Watanabe Immuno-PCR Assay for Homodimeric Osteoprotegerin Clin. Chem., August 1, 2001; 47(8): 1475 - 1477. [Full Text] [PDF]
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T. Yamane, T. Kunisada, H. Tsukamoto, H. Yamazaki, H. Niwa, S. Takada, and S.-I. Hayashi Wnt Signaling Regulates Hemopoiesis Through Stromal Cells J. Immunol., July 15, 2001; 167(2): 765 - 772. [Abstract] [Full Text] [PDF]
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P. Szulc, L. C. Hofbauer, A. E. Heufelder, S. Roth, and P. D. Delmas Osteoprotegerin Serum Levels in Men: Correlation with Age, Estrogen, and Testosterone Status J. Clin. Endocrinol. Metab., July 1, 2001; 86(7): 3162 - 3165. [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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T. Ikeda, M. Kasai, M. Utsuyama, and K. Hirokawa Determination of Three Isoforms of the Receptor Activator of Nuclear Factor-{{kappa}}B Ligand and Their Differential Expression in Bone and Thymus Endocrinology, April 1, 2001; 142(4): 1419 - 1426. [Abstract] [Full Text]
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D. Chen, N. A. Sarikaya, H. Gunn, S. W. Martin, and J. D. Young ELISA Methodology for Detection of Modified Osteoprotegerin in Clinical Studies Clin. Chem., April 1, 2001; 47(4): 747 - 749. [Full Text] [PDF]
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N. Sasaki, E. Kusano, Y. Ando, K. Yano, E. Tsuda, and Y. Asano Glucocorticoid decreases circulating osteoprotegerin (OPG): possible mechanism for glucocorticoid induced osteoporosis Nephrol. Dial. Transplant., March 1, 2001; 16(3): 479 - 482. [Abstract] [Full Text] [PDF]
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Y. Asou, S. R. Rittling, H. Yoshitake, K. Tsuji, K. Shinomiya, A. Nifuji, D. T. Denhardt, and M. Noda Osteopontin Facilitates Angiogenesis, Accumulation of Osteoclasts, and Resorption in Ectopic Bone Endocrinology, March 1, 2001; 142(3): 1325 - 1332. [Abstract] [Full Text] [PDF]
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R. Wang, L. Zhang, X. Zhang, J. Moreno, X. Luo, M. Tondravi, and Y. Shi Differential Regulation of the Expression of CD95 Ligand, Receptor Activator of Nuclear Factor-{{kappa}}B Ligand (RANKL), TNF-Related Apoptosis-Inducing Ligand (TRAIL), and TNF-{{alpha}} During T Cell Activation J. Immunol., February 1, 2001; 166(3): 1983 - 1990. [Abstract] [Full Text] [PDF]
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R. J. Leach, F. R. Singer, and G. D. Roodman The Genetics of Paget's Disease of the Bone J. Clin. Endocrinol. Metab., January 1, 2001; 86(1): 24 - 28. [Full Text]
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Y. Sakuma, K. Tanaka, M. Suda, Y. Komatsu, A. Yasoda, M. Miura, A. Ozasa, S. Narumiya, Y. Sugimoto, A. Ichikawa, et al. Impaired Bone Resorption by Lipopolysaccharide In Vivo in Mice Deficient in the Prostaglandin E Receptor EP4 Subtype Infect. Immun., December 1, 2000; 68(12): 6819 - 6825. [Abstract] [Full Text] [PDF]
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M. Takami, N. Takahashi, N. Udagawa, C. Miyaura, K. Suda, J.-T. Woo, T. J. Martin, K. Nagai, and T. Suda Intracellular Calcium and Protein Kinase C Mediate Expression of Receptor Activator of Nuclear Factor-{{kappa}}B Ligand and Osteoprotegerin in Osteoblasts Endocrinology, December 1, 2000; 141(12): 4711 - 4719. [Abstract] [Full Text] [PDF]
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G.E. Wise, S.J. Lumpkin, H. Huang, and Q. Zhang Osteoprotegerin and Osteoclast Differentiation Factor in Tooth Eruption Journal of Dental Research, December 1, 2000; 79(12): 1937 - 1942. [Abstract] [PDF]
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S. R Goldring The final pathogenetic steps in focal bone erosions in rheumatoid arthritis Ann Rheum Dis, November 1, 2000; 59(90001): i72 - 74. [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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A. Yamaguchi, T. Komori, and T. Suda Regulation of Osteoblast Differentiation Mediated by Bone Morphogenetic Proteins, Hedgehogs, and Cbfa1 Endocr. Rev., August 1, 2000; 21(4): 393 - 411. [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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H. Mano, C. Kimura, Y. Fujisawa, T. Kameda, M. Watanabe-Mano, H. Kaneko, T. Kaneda, Y. Hakeda, and M. Kumegawa Cloning and Function of Rabbit Peroxisome Proliferator-activated Receptor delta /beta in Mature Osteoclasts J. Biol. Chem., March 10, 2000; 275(11): 8126 - 8132. [Abstract] [Full Text] [PDF]
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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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T. Yamashita, H. Yoshitake, K. Tsuji, N. Kawaguchi, Y.-i. Nabeshima, and M. Noda Retardation in Bone Resorption after Bone Marrow Ablation in Klotho Mutant Mice Endocrinology, January 1, 2000; 141(1): 438 - 445. [Abstract] [Full Text] [PDF]
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I Itonaga, A Sabokbar, D W Murray, and N A Athanasou Effect of osteoprotegerin and osteoprotegerin ligand on osteoclast formation by arthroplasty membrane derived macrophages Ann Rheum Dis, January 1, 2000; 59(1): 26 - 31. [Abstract] [Full Text]
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F. Arai, T. Miyamoto, O. Ohneda, T. Inada, T. Sudo, K. Brasel, T. Miyata, D. M. Anderson, and T. Suda Commitment and Differentiation of Osteoclast Precursor Cells by the Sequential Expression of C-Fms and Receptor Activator of Nuclear Factor {kappa}b (Rank) Receptors J. Exp. Med., December 20, 1999; 190(12): 1741 - 1754. [Abstract] [Full Text] [PDF]
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R. Okazaki, M. Toriumi, S. Fukumoto, M. Miyamoto, T. Fujita, K. Tanaka, and Y. Takeuchi Thiazolidinediones Inhibit Osteoclast-Like Cell Formation and Bone Resorption in Vitro Endocrinology, November 1, 1999; 140(11): 5060 - 5065. [Abstract] [Full Text]
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L. C. Hofbauer, F. Gori, B. L. Riggs, D. L. Lacey, C. R. Dunstan, T. C. Spelsberg, and S. Khosla Stimulation of Osteoprotegerin Ligand and Inhibition of Osteoprotegerin Production by Glucocorticoids in Human Osteoblastic Lineage Cells: Potential Paracrine Mechanisms of Glucocorticoid-Induced Osteoporosis Endocrinology, October 1, 1999; 140(10): 4382 - 4389. [Abstract] [Full Text]
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R. J. Thomas, T. A. Guise, J. J. Yin, J. Elliott, N. J. Horwood, T. J. Martin, and M. T. Gillespie Breast Cancer Cells Interact with Osteoblasts to Support Osteoclast Formation Endocrinology, October 1, 1999; 140(10): 4451 - 4458. [Abstract] [Full Text]
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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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S.-K. Lee and J. A. Lorenzo Parathyroid Hormone Stimulates TRANCE and Inhibits Osteoprotegerin Messenger Ribonucleic Acid Expression in Murine Bone Marrow Cultures: Correlation with Osteoclast-Like Cell Formation Endocrinology, August 1, 1999; 140(8): 3552 - 3561. [Abstract] [Full Text]
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T. A. Hentunen, S. H. Jackson, H. Chung, S. V. Reddy, J. Lorenzo, S. J. Choi, and G. D. Roodman Characterization of Immortalized Osteoclast Precursors Developed from Mice Transgenic for Both bcl-XL and Simian Virus 40 Large T Antigen Endocrinology, July 1, 1999; 140(7): 2954 - 2961. [Abstract] [Full Text]
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T. Suda, N. Takahashi, N. Udagawa, E. Jimi, M. T. Gillespie, and T. J. Martin Modulation of Osteoclast Differentiation and Function by the New Members of the Tumor Necrosis Factor Receptor and Ligand Families Endocr. Rev., June 1, 1999; 20(3): 345 - 357. [Abstract] [Full Text]
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L. Lum, B. R. Wong, R. Josien, J. D. Becherer, H. Erdjument-Bromage, J. Schlondorff, P. Tempst, Y. Choi, and C. P. Blobel Evidence for a Role of a Tumor Necrosis Factor-alpha (TNF-alpha )-converting Enzyme-like Protease in Shedding of TRANCE, a TNF Family Member Involved in Osteoclastogenesis and Dendritic Cell Survival J. Biol. Chem., May 7, 1999; 274(19): 13613 - 13618. [Abstract] [Full Text] [PDF]
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 T. L. Burgess, Y.-x. Qian, S. Kaufman, B. D. Ring, G. Van, C. Capparelli, M. Kelley, H. Hsu, W. J. Boyle, C. R. Dunstan, et al. The Ligand for Osteoprotegerin (OPGL) Directly Activates Mature Osteoclasts J. Cell Biol., May 3, 1999; 145(3): 527 - 538. [Abstract] [Full Text] [PDF]
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H. Hsu, D. L. Lacey, C. R. Dunstan, I. Solovyev, A. Colombero, E. Timms, H.-L. Tan, G. Elliott, M. J. Kelley, I. Sarosi, et al. Tumor necrosis factor receptor family member RANK mediates osteoclast differentiation and activation induced by osteoprotegerin ligand PNAS, March 30, 1999; 96(7): 3540 - 3545. [Abstract] [Full Text] [PDF]
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I. Nakamura, H. Tanaka, G. A. Rodan, and L. T. Duong Echistatin Inhibits the Migration of Murine Prefusion Osteoclasts and the Formation of Multinucleated Osteoclast-Like Cells Endocrinology, December 1, 1998; 139(12): 5182 - 5193. [Abstract] [Full Text] [PDF]
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T. J. Yun, P. M. Chaudhary, G. L. Shu, J. K. Frazer, M. K. Ewings, S. M. Schwartz, V. Pascual, L. E. Hood, and E. A. Clark3 OPG/FDCR-1, a TNF Receptor Family Member, Is Expressed in Lymphoid Cells and Is Up-Regulated by Ligating CD40 J. Immunol., December 1, 1998; 161(11): 6113 - 6121. [Abstract] [Full Text] [PDF]
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B. R. Wong, R. Josien, S. Y. Lee, M. Vologodskaia, R. M. Steinman, and Y. Choi The TRAF Family of Signal Transducers Mediates NF-kappa B Activation by the TRANCE Receptor J. Biol. Chem., October 23, 1998; 273(43): 28355 - 28359. [Abstract] [Full Text] [PDF]
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