The Role of Receptor Activator of Nuclear Factor-
B Ligand and Osteoprotegerin in the Pathogenesis and Treatment of Metabolic Bone Diseases1
Lorenz C. Hofbauer and
Armin E. Heufelder
Division of Gastroenterology and Endocrinology, Zentrum für
Innere Medizin, Philipps University, D-35033 Marburg,
Germany
Address all correspondence and requests for reprints to: Lorenz C. Hofbauer, M.D., Division of Gastroenterology and Endocrinology, Zentrum für Innere Medizin, Philipps University, Baldingerstrasse, D-35033 Marburg, Germany. E-mail:
hofbauer{at}post.med.uni-marburg.de
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Introduction
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BONE IS permanently turned over by the
balanced and coordinated action of bone-resorbing osteoclasts and
bone-forming osteoblasts, resulting in continuous renewal, functional
response to external and internal stimuli, and structural integrity
(1, 2, 3). Inappropriate bone resorption caused by enhanced osteoclast
formation and activity has been previously implicated in the
pathogenesis of many metabolic bone diseases. Strategies to inhibit
bone resorption have emerged as potent and promising tools for the
prevention and treatment of bone and mineral disorders (1, 2, 3). The
recent discovery and characterization of a novel cytokine system, the
tumor necrosis factor (TNF) ligand family member, receptor
activator of nuclear factor-
B
ligand (RANKL/OPGL/ODF/TRANCE)
(4, 5, 6, 7);2 its receptor,
receptor activator of nuclear factor
B (RANK/ODAR) (7); and its soluble (decoy) receptor,
osteoprotegerin (OPG/OCIF/TR1)
(8, 9, 10, 11), has established a novel paradigm of osteoclast biology: RANKL,
RANK, and OPG constitute the three essential regulatory components of
osteoclast formation, fusion, survival, activation, and apoptosis
(12, 13, 14). This article3
reviews the molecular aspects of this novel cytokine system and its
regulation and modulation by various osteotropic agents. Moreover, we
summarize the implications of this cytokine system on the pathogenesis
of various bone diseases and discuss the therapeutic potential of OPG
in the clinical setting.
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RANKL/OPGL/ODF/TRANCE: the ligand
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The TNF ligand family member,
osteoprotegerin ligand
(OPGL)/osteoclast differentiation
factor (ODF) was discovered in 1998 by two groups (4, 5) as
the cognate ligand for OPG/osteoclastogenesis
inhibitory factor (OCIF) (8, 9). This factor had
been identified by the same two groups the year before and was shown to
be identical to TNF-related
activation-induced cytokine
(TRANCE) (6) and receptor activator of
nuclear factor-
B ligand (RANKL) (7). RANKL
will be the preferred term according to a consensus nomenclature (12).
RANKL is a cell-bound polypeptide of 317 amino acids (4, 5) that is
cleaved by a protease, TNF
-converting
enzyme-like protease (TACE) (15), at position 140 or 145,
respectively, to give rise to a shorter soluble ectodomain variant of
similar activity (4, 15).
The major sources of RANKL production in the bone/bone marrow
microenvironment are bone marrow stromal cells, osteoblasts,
chondrocytes, mesenchymal cells of the periosteum, osteoclasts,
endothelial cells, and T cells (4, 5, 6, 7, 16). Detailed analyses of its
extraskeletal tissue distribution revealed RANKL messenger ribonucleic
acid (mRNA) and protein production in brain, heart, kidney, skeletal
muscle, and skin (16). Of note, RANKL production is highest in
undifferentiated stromal cells and is greatly reduced once these
multipotential mesenchymal cells become terminally committed to the
osteoblastic phenotype (17, 18, 19). Interestingly, the RANKL gene promoter
structure contains both vitamin D and glucocorticoid response elements
as well as a binding site for the essential osteoblastic transcription
factor, cbfa-1 (20, 21, 22).
In a series of in vitro experiments, RANKL was
consistently shown to stimulate the differentiation, survival, and
fusion of osteoclastic precursor cells, to activate mature osteoclasts,
and to prolong their life span by inhibiting apoptosis (4, 5, 23, 24, 25, 26, 27),
thus expanding the pool of active osteoclasts capable of forming
resorption lacunae (Fig. 1
). In the
presence of permissive levels of macrophage colony-stimulating factor
(M-CSF), RANKL is both sufficient and necessary for all steps of
osteoclast development (28) (Fig. 1
). Of note, other factors, such as
transforming growth factor-ß and PGE2, may
cooperate and synergize with RANKL (29, 30), although the precise roles
of these factors in osteoclast biology are not well defined.

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Figure 1. Regulation of osteoclast functions by RANKL,
OPG, and RANK. Osteoblastic cells express a cell-bound and a soluble
form of RANKL as well as the soluble neutralizing receptor, OPG. RANKL
and OPG have opposite effects on osteoclast biology. 1) Multipotential
macrophagic lineage cells are stimulated by M-CSF, which binds to its
receptor c-fms to proliferate and to become osteoclast
precursor cells. 2) Under permissive levels of M-CSF, binding of
osteoblast-derived RANKL to the receptor RANK induces differentiation
of osteoclast precursors to prefusion osteoclasts. OPG blocks this
effect by neutralizing RANKL. 3) Survival and fusion are stimulated by
RANKL, a process that yields multinucleated osteoclasts and is
modulated by cytokines such as IL-1, TNF , and IL-6 and is inhibited
by OPG. 4) Osteoclasts are activated by RANKL (as well as IL-1, TNF ,
and IL-6) and become capable of resorbing bone. This is blocked by OPG.
5) Mature osteoclasts undergo apoptosis, which is induced by OPG and
prevented by RANKL.
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Consistent with these effects, parenteral administration of recombinant
RANKL to mice in vivo resulted in severe osteoporosis
associated with increased osteoclastic activity (as assessed by a
doubling of the resorption surface), rapid bone loss, and severe
hypercalcemia (4). By contrast, mice rendered deficient in RANKL by
targeted ablation have severe osteopetrosis, impaired tooth eruption,
and a lack of mature osteoclasts, indicating that RANKL is required for
osteoclast differentiation and activation (31). Of note, RANKL
deficiency also results in defects of B and T lymphocyte maturation
(lymph node agenesis, thymus hypoplasia) (31).
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RANK: the receptor
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The effects of RANKL are mediated by binding to and activating its
specific high affinity receptor, receptor
activator of nuclear factor (NF)-
B
(RANK)/osteoclast differentiation and
activation receptor (ODAR; Fig. 1
) (7, 32). RANK,
a type I transmembrane protein composed of 616 amino acids, contains 4
cysteine-rich pseudorepeats, a characteristic feature of the TNF
receptor (TNFR) superfamily (7, 32, 33). RANK expression is largely
limited to osteoclasts, T and B cells, dendritic cells, and fibroblasts
(7, 32, 33).
RANK activation involves RANKL-dependent interaction with
TNFR-associated factor
(TRAF) family members, the transcription factors NF-
B and c-Fos,
c-Jun N-terminal kinase (JNK), the protooncogene c-src, and
the antiapoptotic serine/threonine kinase Akt/PKB. Stimulating
antibodies directed against the extracellular domains of RANK mimicked
the action of RANKL and induced osteoclastogenesis in vitro,
whereas inhibitory fragments of this RANK antibody or a soluble RANK
variant (which compete with the cell-bound RANK for RANKL) blocked
osteoclastogenesis (32, 33).
Various in vivo models support RANK as an essential
requirement for normal osteoclastic differentiation and activation.
Transgenic mice overexpressing soluble RANK displayed an osteopetrotic
phenotype due to decreased osteo-clastogenesis (32). In addition,
RANK knockout mice revealed a phenotype characterized by osteopetrosis
and associated immune defects (38, 39), which is similar to the
phenotype observed in RANKL-deficient mice (31). Moreover, mice
subjected to targeted ablation of downstream elements of the RANK
pathway, such as TRAF-6 (40) and NF-
B1/NF-
B2 (41), also have an
osteopetrotic phenotype, clearly establishing the RANK signaling
pathway as the key gatekeeper of osteoclast differentiation and
activation.
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OPG: the decoy receptor
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Osteoprotegerin
(OPG)/osteoclastogenesis inhibitory
factor (OCIF) were independently discovered by two groups in
1997 as the first component of this novel cytokine system (8, 9, 42).
Other investigators have since confirmed these data and named it
TNF receptor-related molecule-1 (TR1)
(10, 11) and follicular dendritic cell
receptor-1 (FDCR-1) (43). OPG is the only known
secreted TNFR member that lacks a transmembrane domain (8, 9, 10, 11). OPG is
a propeptide of 401 amino acids with a short signal peptide (21 amino
acids) that forms homodimers linked through a cystein-cystein disulfide
bond at position 400 (8, 9, 10, 11). One study suggests that OPG may also
exist in a membrane-bound form on the surface of a follicular dendritic
cell line (43). In contrast to RANKL and RANK, whose abundance is
generally low and whose expression is mainly restricted to the skeletal
and immune system, OPG is expressed in high concentrations by a variety
of tissues and cell types (8, 9, 10, 11, 42, 43, 44, 45). In bone, OPG is mainly
produced by cells of the osteoblastic lineage, with increasing
production as the cells become more differentiated (16, 17, 18, 45, 46).
OPG is a decoy receptor that acts by binding to and neutralizing both
the soluble and the cell-bound form of RANKL (8, 9) and that of another
TNF ligand family member, TRAIL (47). In vitro, OPG inhibits
the differentiation, survival, and fusion of osteoclastic precursor
cells, blocks activation of mature osteoclasts, and induces osteoclast
apoptosis (4, 5, 11, 26, 27, 42, 46, 47, 48, 49, 50, 51) (Fig. 1
).
In vivo, manipulation of OPG production has generated both
extremes of skeletal phenotypes, osteopetrosis and osteoporosis.
Overexpression of OPG in transgenic mice (in which the transgene is
activated after birth) is associated with severe osteopetrosis (8),
similar to that in RANKL (31) and RANK knockout mice (38, 39), but
without the associated immune abnormalities observed in the latter two
animal models. In contrast, mice with targeted ablation of OPG have
severe, early-onset osteoporosis due to enhanced osteoclastic activity
(52, 53). Of note, one study also revealed severe arterial
calcification in OPG-deficient mice (52), indicating a protective role
for OPG in the vascular system. Parenteral administration of
recombinant OPG to normal rodents resulted in increased bone mass (8, 9), and completely prevented ovariectomy-induced bone loss (8) without
apparent adverse skeletal and extraskeletal side effects. These
successful initial studies have formed the theoretical background for
the potential use of OPG as an antiresorptive agent.
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Triangular regulation by RANKL, RANK, and OPG
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Identification of the three components, RANKL, RANK, and OPG, the
subsequent characterization of their effects in vitro and
in vivo, and characterization of transgenic and knockout
models have unambiguously established this novel cytokine system as the
essential and final effector system of osteoclast biology (Fig. 1
)
(reviewed in Refs. 12, 13, 14). In the skeleton, RANKL and OPG are mainly
produced by cells of the osteoblastic lineage, whereas RANK is
expressed by osteoclasts. The RANKL/OPG ratio is highest in
undifferentiated preosteoblastic cells and decreases with osteoblastic
differentiation (17, 18, 19) (which is paralleled by a decreasing capacity
to support osteoclastogenesis). Because the RANKL gene promoter
contains a binding site for the osteoblastic transcription factor,
cbfa-1 (20, 21, 22), it has been concluded that osteoclast
formation is coupled to osteoblast differentiation through
cbfa-1 and RANKL. This concept may plausibly explain the
sequential cycle of bone resorption and formation during bone
remodeling (Fig. 1
).
As mentioned earlier, RANKL-induced activation of RANK and its
second messenger system is both necessary and sufficient for all
aspects of osteoclast ontogeny, and only the initial step
(osteoclastogenesis) requires permissive levels of M-CSF (12, 13, 14).
Previous studies have suggested a role for interleukin-1 (IL-1),
TNF
, and IL-6 as other important proresorptive cytokines (54, 55, 56).
Recent reports suggest that these cytokines, in addition to modulating
RANKL, OPG, or both (see below), may directly modulate osteoclast
differentiation and activation through RANKL- and RANK-independent
mechanisms (57, 58, 59, 60). Further studies are required to fully understand
how these various cytokines and their signaling cascades converge at or
circumvent the RANKL-RANK-NF-
B pathway.
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Regulation of the RANKL/OPG system by calcitropic agents
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Because the RANKL/OPG ratio is an essential determinant of
osteoclast biology, any agent that regulates RANKL, OPG, or both, is
likely to indirectly modulate osteoclast differentiation, activation,
and apoptosis (12, 13, 14). Various peptide and steroid hormones, growth
factors, cytokines, drugs, and ions have been shown to regulate the
RANKL/OPG system in different stromal and osteoblastic cell models
(Table 1
), and changes in the RANKL/OPG
ratio were found to be associated with altered osteoclast
differentiation and activation.
Among the factors that increase RANKL mRNA expression in
osteoblastic cells are the proinflammatory cytokines, IL-1, IL-6,
IL-11, oncostatin, TNF
, and PGE2 (5, 61, 62, 63),
and the steroid hormones, dexamethasone and 1
,25-dihydroxyvitamin
D3
[1,25-(OH)2D3] (5, 46, 62, 64, 65). In addition, RANKL gene expression is enhanced by PTH (5, 25, 64, 66, 67) as well as by commonly used immunosuppressants
(cyclosporin A, rapamycin, and tacrolimus) (68). Furthermore, some of
the RANKL-stimulating factors have not been previously shown to be
regulators of osteoclastogenesis and osteoclast activation. These
include Indian hedgehog (69), fibroblast growth factor-2 (70),
autocrine motility factor (71), bone morphogenetic protein-7 (72), and
intracellular calcium cations (73). Factors that inhibit RANKL
expression include transforming growth factor-ß (74), inhibin (75),
and vasoactive intestinal peptide (76).
OPG production is stimulated by the proinflammatory cytokines, IL-1 and
TNF (11, 45, 61, 77, 78), transforming growth factor-ß (73, 79), bone
morphogenetic protein-2 (45) and -7 (72),
1
,25-(OH)2D3 (45),
17ß-estradiol (80, 81), vasoactive intestinal peptide (76), and
calcium cations (9). OPG production is decreased by
PGE2 (82); glucocorticoids (44, 46, 65);
1
,25-(OH)2D3 (64, 79);
the immunosuppressants cyclosporin A, rapamycin, and tacrolimus (68);
the pure estrogen receptor antagonist ICI 182,780 (80); and PTH (66, 79).
Although RANKL and OPG are regulated by various factors (Table 1
), RANK
expression on osteoclastic cells was found to be stable, with little
regulation by osteotropic agents (83). However, in the immune systems,
RANK expression on T cells is up-regulated by IL-4 and transforming
growth factor-ß, and RANK expression on dendritic cells is
down-regulated by CD40 ligand (7).
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OPG/RANKL and the pathogenesis of metabolic bone diseases
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Osteoporosis associated with estrogen deficiency. Several
cytokines (IL-1, TNF
, IL-6, and M-CSF) have been implicated in the
pathogenesis of postmenopausal osteoporosis, because their expression
or activity is up-regulated by estrogen deficiency and down-regulated
by estrogen administration (54, 55, 56). The early phase of estrogen
deficiency (58 yr after menopause) is associated with enhanced
osteoclastogenesis and bone resorption and results in rapid bone loss
(84). Several lines of evidence suggest that RANKL and OPG may mediate
at least in part some of the antiresorptive effects of estrogen. First,
estrogen stimulates the expression of OPG in osteoblastic (80) and
stromal cells (81) via transcriptional activation of ER-
. Second,
estrogen deficiency in ovariectomized rodents results in decreased OPG
expression (85, 86) and increases RANKL production (86, 87) by cells of
the bone and bone marrow microenvironment, whereas estrogen replacement
therapy prevents it (85). As mentioned previously, OPG administration
completely abolishes ovariectomy-induced bone loss in rodents (8).
Third, estrogen treatment inhibits the responsiveness of osteoclastic
precursor cells to the actions of RANKL (88, 89), possibly by blunting
RANKL-induced JNK activation (88).
Despite this compelling experimental evidence, epidemiological studies
have generated conflicting data. In one study, which observed a small
increase in serum OPG levels in osteoporotic vs.
nonosteoporotic postmenopausal women (90), it was hypothesized that
elevated OPG levels may compensate for increased bone resorption. By
contrast, another study has failed to confirm this (91).
Drug-induced osteoporosis. Glucocorticoid-induced
osteoporosis is the most frequent secondary form of osteoporosis.
Various cytokines have been suggested as mediators of the increase in
osteoclastic bone resorption that usually occurs within the first few
months after initiation of glucocorticoid treatment (92, 93). In
vitro, glucocorticoids down-regulate OPG production via a
transcriptional mechanism (44, 46, 65, 79) and up-regulate RANKL
expression (5, 46, 62, 64, 65) in osteoblastic cells, possibly by
activating the glucocorticoid response element of the RANKL gene
promoter (21). This marked increase in the osteoblastic RANKL/OPG ratio
after glucocorticoid exposure is associated with enhanced
osteoclastogenesis (46). The inhibitory effect of glucocorticoids on
serum OPG levels (94) suggests that OPG deficiency after glucocorticoid
excess may promote rapid bone loss in vivo (95).
Immunosuppressants are also known to induce rapid bone loss in
recipients of allogeneic organ transplants. These agents have been
found to increase RANKL expression and decrease OPG production in human
marrow stromal cells and to induce osteoclastogenesis (68).
Hyperparathyroidism. Continuously increased and unregulated
serum PTH concentrations, as present in hyperparathyroidism, result in
increased bone resorption and bone loss (96). In vitro, PTH
was found to stimulate RANKL mRNA levels (5, 25, 64, 66, 67), to
decrease OPG production in osteoblastic cells (66, 79), and to increase
the RANKL/OPG ratio (64, 66). All of these changes were associated with
increased osteoclast formation (66). It is unclear whether intermittent
exposure to PTH (which may have anabolic effects on bone in
vivo), rather than continuous exposure, leads to a favorable
change in the RANKL/OPG ratio.
Pagets disease. Pagets disease is characterized by
uncontrolled bone remodeling due to increased bone resorption by
osteoclasts (97). A hyperosteoclastogenic bone marrow microenvironment
due to abnormal production of or response to cytokines (IL-6) and
hormones [1,25(OH)2D3],
perhaps triggered by the presence of paramyxoviral-like nuclear
inclusions, has been suggested as a potential mechanism (97). Only
recently, enhanced RANKL expression was observed in a bone marrow
stromal cell line developed from a patient with Pagets disease (98).
Furthermore, osteoclastic precursor cells harvested from affected
lesions were found to have increased sensitivity toward the effects of
RANKL (98, 99). Thus, local overexpression of RANKL and/or local
hypersensitivity to the effects of RANKL may account for the highly
localized pattern of Pagets disease in bone (98).
Bone loss associated with rheumatoid arthritis. Systemic
osteoporosis and local periarticular bone loss adjacent to affected
joints are common in patients with rheumatoid arthritis and have been
attributed to high circulating and local levels of proinflammatory
cytokines (55, 100). Activated CD4+ helper cells,
which constitute a major population of immune cells in the inflamed
synovium in rheumatoid arthritis, have been shown to produce RANKL and
to support osteoclastogenesis in vitro (101, 102). In addition,
systemic activation of T cells resulted in RANKL-mediated osteoclast
formation and bone loss in vivo. (101). Moreover, in rat adjuvant
arthritis, a T cell-dependent animal model of rheumatoid arthritis,
neutralization of RANKL by exogenous administration of OPG prevented
bone loss and cartilage damage (101). Increased RANKL production has
also been demonstrated in synovial fibroblasts derived from patients
with rheumatoid arthritis (103, 104), but not in subjects with other
forms of arthritis, and this was associated with increased
osteoclastogenesis (103). In addition, OPG levels in the synovial fluid
of patients with rheumatoid arthritis (but not other joint diseases)
are inappropriately low (105), which may limit the capacity to
counteract the detrimental effects of RANKL on enhanced
osteoclastogenesis at the sites of active joint disease. Interestingly,
the effects of IL-17, a potent stimulator of osteoclastogenesis in
rheumatoid arthritis, could be inhibited by OPG in vitro (106),
indicating a potential therapeutic avenue for severe rheumatoid
arthritis.
Osteopetrosis. Osteopetrosis is a rare polygenic disorder of
generalized increased bone mass due to decreased osteoclastogenesis and
bone resorption (107). Although the RANKL/OPG system has not directly
been implicated in human osteopetrotic syndromes, several animal models
indicate that RANKL, OPG, and their signaling pathway may play a
potential role in the pathogenesis of osteopetrosis. For instance, mice
deficient in RANKL (31), RANK (38, 39), TRAF-6 (40), and
NF-
B1/NF-
B2 (41) have severe osteopetrosis. Moreover, transgenic
mice overexpressing either OPG (8) or soluble RANK (32), both of which
neutralize RANKL, also have osteopetrosis. Of note, a stop mutation in
the coding region of the gene for M-CSF (which is the permissive factor
for the effects of RANKL; see Fig. 1
) has been previously detected in
the murine model of spontaneous osteopetrosis (108).
Bone tumors and bone metastases. Abnormalities of the
RANKL/RANK/OPG system have been suggested to be involved in the
evolution of benign and malignant bone tumors and in the development of
osteolytic lesions by tumor metastases. Osteoclastomata (giant cell
tumors) are lytic lesions of the epiphyses of long bones. Stromal cells
of affected lesions (109, 110) and synovial fibroblasts of patients
with giant cell tumor (103) were found to produce high levels of
transcripts for RANKL as well as for M-CSF (110), whereas giant cells
of affected lesions produced high levels of RANK (109, 110). Increased
RANKL mRNA expression has been detected in cell lines of multiple
myeloma, which is commonly associated with osteolysis and hypercalcemia
(111), whereas tissue harvested from sporadic osteosarcoma revealed a
loss of RANKL expression, consistent with decreased perilesional bone
resorption (112).
Several groups have clearly demonstrated that breast cancer cells (by
secreting PTH-related peptide) indirectly stimulate stromal cells and
osteoblasts to increase RANKL production (113, 114, 115, 116) and to limit OPG
production (113, 114), thus leading to increased formation, activation,
and survival of osteoclasts. In addition, the propensity of prostate
cancer cell lines to cause either osteolytic or osteoblastic metastases
was correlated with either a higher (osteolytic) or a lower
(osteoblastic) RANKL/OPG ratio produced by prostate cancer cells
compared to normal prostate cells (117).
Miscellaneous. Other diseases in which the RANKL/RANK/OPG
system may play a role include familial expansile osteolysis, a rare
autosomal dominant disorder characterized by focal areas of enhanced
bone resorption (118), and its murine equivalent, chronic multifocal
osteomyelitis (119), both of which are due to a gain of function
mutation, leading to constitutive activation of RANK. Of note, a
similar mechanism is also present in patients with familial Pagets
disease of bone (118). Other potential RANKL/RANK/OPG-dependent bone
diseases include disuse osteoporosis (up-regulation of RANKL by a lack
of mechanical strain, which down-regulates RANKL) (120) and periodontal
disease (modulation of RANKL and OPG by proinflammatory cytokines in
dental cells) (121). RANKL and OPG may also play a role in vascular
calcification and atherogenesis, because these factors are produced by
vascular smooth muscle cells (68) and endothelial cells (122) and are
regulated by various hormones and cytokines (68, 122). Moreover,
OPG-deficient mice reveal severe arterial calcification (52).
 |
Potential therapeutic role of OPG in bone diseases
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Administration of recombinant OPG to animals. The pronounced
antiresorptive and bone mass-enhancing effects of OPG in
vivo has been initially described by two groups (8, 9). Simonet
et al. (8) reported a 3-fold increase in bone mass in young
mice after treatment with OPG (10 mg/kg·day for 7 days), and Yasuda
et al. (9) observed a 1.8-fold increase in bone mass in
young rats after treatment with OPG (24 mg/kg·day for 14 days).
Subsequent studies confirmed the antiresorptive and hypocalcemic
effects of parenteral administration of OPG in normal rodents with
physiological bone resorption (123, 124). In addition, OPG was also
shown to suppress enhanced bone resorption in rodents. In their initial
paper, Simonet et al. reported that OPG treatment (5
mg/kg·day for 14 days) completely prevented ovariectomy-induced bone
loss in rats (8). Subsequently, OPG was shown to inhibit increased bone
resorption during normal linear bone growth (125); after challenge with
IL-1ß, TNF
, PTH, PTHrP,
1,25-(OH)2D3 (125, 126),
and RANKL (4); and after challenge with PTH or
1
,25-(OH)2D3 after
thyroparathyroidectomy (127). Of note, in some of these studies, OPG
also completely controlled associated hypercalcemia (4, 126). Similar
effects have been shown for soluble RANK, which neutralizes RANKL, but
not TRAIL (128).
These studies have generated the hypothesis that OPG may be useful for
treatment of bone and mineral abnormalities in animal tumor models. OPG
(124, 125, 129, 130) and soluble RANK (128) were found to control
increased bone resorption and hypercalcemia in rodent models of humoral
hypercalcemia of malignancy. Overall, treatment with OPG was well
tolerated; had a rapid, marked, and long-lasting hypocalcemic effect;
and was devoid of apparent adverse effects (124, 125, 128, 129, 130). OPG
administration was also capable of preventing and suppressing
osteolysis and hypercalcemia in animal models with bone metastases due
to colonic and breast cancer (131).
Finally, OPG prevented increased bone loss associated with
immobilization and disuse osteoporosis (132, 133). OPG was more potent
compared to the bisphosphonates pamidronate and ibandronate in
preventing bone loss in both the sciatic nerve crush model (132) and
the tail suspension model (133).
Administration of recombinant OPG to humans. The
beneficial effects, safety, and tolerability of OPG have been recently
demonstrated in a randomized, double blind, placebo-controlled clinical
study on 52 postmenopausal women (134). A single sc dose of human
recombinant OPG (3 mg/kg) reduced biochemical markers of bone
resorption (deoxypyridinolines, -80% by day 5) and of bone formation
(osteocalcin, -20% by day 29), indicating the potential of a marked
and prolonged suppression of increased bone turnover. Except for a
modest decrease in serum and urinary calcium concentrations with a
subsequent increase in serum PTH levels, no other laboratory
abnormalities were observed (134). The pharmacokinetic profile of OPG
indicates that serum levels peak between 2448 h after sc
administration and then decrease, with a terminal half-life of 3847 h
(135). The volume of distribution of recombinant human OPG is between
3741 ml/kg after iv administration, which suggests that OPG does not
distribute into the extravascular compartment (135).
 |
Conclusions
|
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RANKL and OPG have emerged as a key agonist/antagonist cytokine
system that regulates important aspects of osteoclast biology,
including differentiation, fusion, survival, activation, and apoptosis.
RANKL increases the pool of active osteoclasts by activating its
specific receptor RANK located on osteoclastic cells, thus increasing
bone resorption, whereas OPG, which neutralizes RANKL, has opposite
effects. RANKL and OPG are produced by bone marrow-derived stromal
cells and osteoblasts and are regulated by various
calcitropic cytokines, hormones, and drugs. Alterations or
abnormalities of the RANKL/OPG system have been implicated in different
metabolic bone diseases characterized by increased osteoclast
differentiation and activation and by enhanced bone resorption (Table 2
). These disorders include postmenopausal osteoporosis,
glucocorticoid-induced osteoporosis, hyperparathyroidism,
Pagets disease, rheumatoid arthritis, and bone malignancies. Animal
studies have suggested that exogenous administration of OPG may prevent
the adverse skeletal effects of ovariectomy, humoral hypercalcemia of
malignancy, osteolytic metastases, and immobilization. Preliminary
results from clinical studies in postmenopausal women indicate that
exogenous administration of OPG is a safe and well tolerated form of
therapy that results in prolonged antiresorptive effects when given
once per month. In view of this rapid progress in our basic
understanding of osteoclast biology and the compelling experimental and
clinical evidence, recombinant OPG will expand our armamentarium of
compounds to fight osteoporosis and other metabolic bone diseases in
the years to come.
 |
Footnotes
|
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1 This work was supported by Grants Ho 1875/11 and Ho 1875/21 (to
L.C.H.) from Deutsche Forschungsgemeinschaft (Bonn, Germany) and by
Grant 10-1697-Ho 1 (to L.C.H.) from Deutsche Krebshilfe (Bonn,
Germany). 
2 The following abbreviations are used: NF-
B,
nuclear factor-
B; OCIF, osteoclastogenesis inhibitory factor; ODAR,
osteoclast differentiation and activation receptor; ODF, osteoclast
differentiation factor; OPG, osteoprotegerin; OPGL, OPG ligand; RANK,
receptor activator of NF-
B; RANKL; RANK ligand; TACE,
TNF
-converting enzyme-like protease; TNF, tumor necrosis factor;
TNFR, TNF receptor; RAF, TNFR-associated factor; TRANCE, TNF-related
activation-induced cytokine. According to a future nomenclature, RANKL
will be referred to as TNF superfamily member TNFSF11, and RANK and OPG
will be referred to as TNF receptor superfamily members TNFRSF-11A and
11B, respectively (see http://www.hugo-international.org). 
3 To present an inclusive and up to date review,
the authors have elected to cite several studies that have only been
published in a preliminary (abstract) format. 
Received December 16, 1999.
Revised March 13, 2000.
Accepted March 21, 2000.
 |
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