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Division of Endocrinology & Metabolism, Center for Osteoporosis & Metabolic Bone Diseases, University of Arkansas for Medical Sciences, and the Central Arkansas Veterans Healthcare System, Little Rock, Arkansas 72205, USA
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Abstract |
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I. Introduction |
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Homer, the Odyssey: translation by Robert Fagles
LOSS OF height (stooping), Dowager’s hump, and kyphosis are some of the most visible signs of old age in humans. The primary reason for these involutional changes is a progressive loss of bone mass that affects the axial (primarily trabecular) as well as the appendicular (primarily cortical) skeleton. Loss of bone mass, along with microarchitectural deterioration of the skeleton, leads to enhanced bone fragility and increased fractures—the bone disease known as osteoporosis (1 ). Both men and women start losing bone in their 40s. However, women experience a rapid phase of loss during the first 5–10 yr after menopause, due to the loss of estrogen (2 ). In men this phase is obscure, since there is only a slow and progressive decline in sex steroid production; hence, the loss of bone in men is linear and slower (3 ). In addition to losing bone faster at the early postmenopausal years, women also accumulate less skeletal mass than men during growth, particularly in puberty, resulting in smaller bones with thinner cortices and smaller diameter. Consequently, the incidence of bone fractures is 2- to 3-fold higher in women as compared with men (4 ).
In addition to sex steroid deficiency and the aging process itself, loss of bone mass is accentuated when several other conditions are present. The most common are chronic glucocorticoid excess (5 ), particularly its iatrogenic form, hyperthyroidism as well as inappropriately high T4 replacement, alcoholism, prolonged immobilization, gastrointestinal disorders, hypercalciuria, some types of malignancy, and cigarette smoking (6 ).
Bone loss and eventually fractures are the hallmarks of osteoporosis, regardless of the underlying cause or causes. The bone loss associated with normal aging in women has been divided into two phases: one that is due to menopause and one that is due to aging and affects men as well (7 8 ). In elderly women these two phases eventually overlap, making it difficult to distinguish the effect of sex steroid deficiency from the effect of the aging process itself. The effect of the aging process itself is also frequently obscured because of secondary hyperparathyroidism (9 ), resulting from impaired calcium absorption from the intestine with advancing age (>75 yr old). The bone loss that is due to glucocorticoid excess shares several features with the bone loss due to senescence, but also has unique features of its own. Nonetheless, as is the case with the other types of bone loss, the heterogeneity of the underlying conditions, some of which (e.g., postmenopausal state, rheumatoid arthritis, etc.) independently contribute to skeletal deterioration, can distort the clinical and histological picture (10 ). Irrespective of the overlap, it is important to recognize that the pathogenetic mechanisms are quite distinct in the various forms of osteoporosis and that sex hormone deficiency and aging have independent effects.
During the last few years, there have been significant advances in our understanding of the pathogenetic mechanisms responsible for the bone loss associated with sex steroid deficiency, old age, and glucocorticoid excess. All these conditions do not cause loss of bone mass by turning on a completely new process. Instead, they cause a derangement in the normal process of bone regeneration. Therefore, to understand the pathogenesis of osteoporosis and rationalize its treatment, one must first appreciate the basic principles of physiological bone regeneration.
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II. Physiological Bone Regeneration |
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A. Remodeling by the basic multicellular unit (BMU)
Removal of bone (resorption) is the task of osteoclasts. Formation
of new bone is the task of osteoblasts. Bone resorption and bone
formation, however, are not separate, independently regulated
processes. In the uninjured adult skeleton, all osteoclasts and
osteoblasts belong to a unique temporary structure, known as a basic
multicellular unit or BMU (13 ). Although during modeling one cannot
distinguish anatomical units analogous to BMU per se,
sculpting of the growing skeleton requires spatial and temporal
orchestration of the destination of osteoblasts and osteoclasts, albeit
with different rules and coordinates to those operating in the BMU of
the remodeling skeleton. The BMU, approximately 1–2 mm long and
0.2–0.4 mm wide, comprises a team of osteoclasts in the front, a team
of osteoblasts in the rear, a central vascular capillary, a nerve
supply, and associated connective tissue (13 ). In healthy human adults,
3–4 million BMUs are initiated per year and about 1 million are
operating at any moment (Table 1
). Each
BMU begins at a particular place and time (origination) and advances
toward a target, which is a region of bone in need of replacement, and
for a variable distance beyond its target (progression) and eventually
comes to rest (termination) (10 ). In cortical bone, the BMU travels
through the bone, excavating and replacing a tunnel. In cancellous
bone, the BMU moves across the trabecular surface, excavating and
replacing a trench. In both situations, the cellular components of the
BMUs maintain a well orchestrated spatial and temporal relationship
with each other. Osteoclasts adhere to bone and subsequently remove it
by acidification and proteolytic digestion. As the BMU advances,
osteoclasts leave the resorption site and osteoblasts move in to cover
the excavated area and begin the process of new bone formation by
secreting osteoid, which is eventually mineralized into new bone.
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). Therefore, continuous supply of new
osteoclasts and osteoblasts from their respective progenitors in the
bone marrow is essential for the origination of BMUs and their
progression on the bone surface. Consequently, the balance between the
supply of new cells and their lifespan are key determinants of the
number of either cell type in the BMU and the work performed by each
type of cells and are critical for the maintenance of bone homeostasis. |
III. Osteoblastogenesis and Osteoclastogenesis |
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The development and differentiation of osteoblasts and osteoclasts are controlled by growth factors and cytokines produced in the bone marrow microenvironment as well as adhesion molecules that mediate cell-cell and cell-matrix interactions. Several systemic hormones as well as mechanical signals also exert potent effects on osteoclast and osteoblast development and differentiation. Although many details remain to be established concerning the operation of this network, a few themes have emerged (21 ). First, several of the growth factors and cytokines control each other’s production in a cascade fashion and, in some instances, form positive and negative feedback loops. Second, there is extensive functional redundancy among them. Third, some of the same factors are capable of influencing the differentiation of both osteoblasts and osteoclasts. Fourth, systemic hormones influence the process of osteoblast and osteoclast formation via their ability to control the production and/or action of local mediators.
A. Growth factors and their antagonists
The only factors capable of initiating osteoblastogenesis from
uncommitted progenitors are bone morphogenetic proteins (BMPs) (22 ).
BMPs have been long implicated in skeletal development during embryonic
life and fracture healing. More recently, it has become apparent that
BMPs, and in particular BMP-2 and –4, also initiate the commitment of
mesenchymal precursors of the adult bone marrow to the osteoblastic
lineage (23 ). BMPs stimulate the transcription of the gene encoding an
osteoblast-specific transcription factor, known as osteoblast specific
factor 2 (Osf2) or core binding factor a1 (Cbfa1), hereafter referred
to as Cbfa1 (24 ). In turn, Cbfa1 activates osteoblast-specific genes
such as osteopontin, bone sialoprotein, type I collagen, and
osteocalcin. The importance of Cbfa1 for osteoblasts has been
highlighted by the evidence that knockout of the Cbfa1 gene in mice
prevents osteoblast development (25 26 ). In addition to Cbfa1, BMP-4
induces a homeobox-containing gene, distal-less 5(Dlx5), which also
seems to act as a transcription factor, probably as a heterodimer with
another homeobox-containing protein (Msx2). Like Cbfa1, Dlx5 regulates
the expression of osteoblast-specific genes such as osteocalcin and
alkaline phosphatase, as well as mineralization (27 28 29 ). Other factors
such as transforming growth factor ß (TGFß), platelet-derived
growth factor (PDGF), insulin-like growth factors (IGFs), and members
of the fibroblast growth factor (FGF) family can all stimulate
osteoblast differentiation (30 31 ). However, whereas TGFß, PDGF,
FGF, and IGFs are able to influence the replication and differentiation
of committed osteoblast progenitors toward the osteoblastic lineage,
they cannot induce osteoblast differentiation from uncommitted
progenitor cells.
In addition to growth factors, bone cells produce proteins that modulate the activity of growth factors either by binding to them and thereby preventing interaction with their receptors, by competing for the same receptors, or by promoting the activity of a particular factor. For example, osteoblasts produce several IGF-binding proteins (IGFBPs). Of these, IGFBP-4 binds to IGF and blocks its action, whereas IGFBP-5 promotes the stimulatory effects of IGF on osteoblasts (30 ). During the last few years, several proteins able to antagonize BMP action have also been discovered. Of them, noggin, chordin, and cerberus were initially found in the Spemann organizer of the Xenopus embryo and shown to be essential for neuronal or head development (32 33 34 35 ). Noggin and chordin inhibit the action of BMPs by binding directly and with high affinity with the latter proteins (36 37 ). Such binding is highly specific for BMP-2 and 4, as noggin binds BMP-7 with very low affinity and does not bind TGFß or IGF-I. Addition of human recombinant noggin to bone marrow cell cultures from normal adult mice inhibits not only osteoblast, but also osteoclast, formation, and these effects can be reversed by exogenous BMP-2 (23 ). Consistent with this evidence, BMP-2 and -4 and BMP-2/4 receptor transcripts and proteins are found in bone marrow cultures and in bone marrow-derived stromal/osteoblastic cell lines, as well as in murine adult whole bone. Noggin expression has also been documented in all these cell preparations. These findings indicate that BMP-2 and -4 are expressed in the bone marrow in postnatal life and serve to maintain the continuous supply of osteoblasts.
B. Cytokines
Since the early stages of hematopoiesis and osteoclastogenesis
proceed along identical pathways, it is not surprising that a large
group of cytokines and colony-stimulating factors that are involved in
hematopoiesis also affect osteoclast development (38 ). This group
includes the interleukins IL-1, IL-3, IL-6, IL-11, leukemia inhibitory
factor (LIF), oncostatin M (OSM), ciliary neurotropic factor (CNTF),
tumor necrosis factor (TNF), granulocyte macrophage-colony stimulating
factor (GM-CSF), M-CSF, and c-kit ligand. As opposed to the above
mentioned cytokines that stimulate osteoclast development, IL-4, IL-10,
IL-18, and interferon-
inhibit osteoclast development. In the case
of IL-18 the effect is mediated through GM-CSF (39 ).
IL-6 has attracted particular attention because of evidence that it
plays a pathogenetic role in several disease states characterized by
accelerated bone remodeling and excessive focal or systemic bone
resorption (40 ). IL-6 is produced at high levels by cells of the
stromal/osteoblastic lineage in response to stimulation by a variety of
other cytokines and growth factors such as IL-1, TNF, TGFß, PDGF, and
IGF-II (41 42 43 ). Binding of IL-6 or other members of the same cytokine
family (IL-11, LIF, OSM) to cytokine-specific cell surface receptors
(in the case of IL-6, the IL-6R
) causes recruitment and homo- or
heterodimerization of the signal transducing protein gp130, which is
then tyrosine phosphorylated by members of the Janus family of tyrosine
kinases (JAKs) (44 ). This event results in tyrosine phosphorylation of
several downstream signaling molecules, including members of the signal
transducers and activators of transcription (STAT) family of
transcription factors (45 46 ). Phosphorylated STATs, in turn, undergo
homo- and heterodimerization and translocate to the nucleus where they
activate cytokine- responsive gene transcription (47 ). The -subunit
of the IL-6 receptor also exists in a soluble form (sIL-6R), but unlike
most soluble cytokine receptors, it functions as an agonist by binding
to IL-6 and then interacting with membrane-associated gp130 to
stimulate JAK/STAT signaling (44 ). On the other hand, the soluble form
of gp130 blocks IL-6 action (48 ).
Alone or in concert with other agents, IL-6 stimulates
osteoclastogenesis and promotes bone resorption. The cells that mediate
the actions of the IL-6 type cytokines on osteoclast formation appear
to be the stromal/osteoblastic cells, as stimulation of IL-6R
expression on these cells allows them to support osteoclast formation
in response to IL-6 (49 ). These findings indicate that the
osteoclastogenic property of IL-6 depends not only on its ability to
act directly on hematopoietic osteoclast progenitors, but also on the
activation of gp130 signaling in the stromal/osteoblastic cells that
provide essential support for osteoclast formation. STAT3 activation in
stromal/osteoblastic cells is essential for gp130-mediated osteoclast
formation (50 ). Despite the effects of IL-6 on osteoclastogenesis in
experimental in vitro systems, IL-6 is not required for
osteoclastogenesis in vivo under normal physiological
conditions. In fact, osteoclast formation is unaffected in sex
steroid-replete mice treated with a neutralizing anti-IL-6 antibody, or
in IL-6-deficient mice (51 52 ). The most likely explanation for this
is that the -subunit of the IL-6 receptor in bone is a limiting
factor, and that both a change in the receptor and the cytokine are
required for the IL-6- mediated increased osteoclastogenesis, seen in
pathological states.
IL-6 type cytokines are capable of influencing the differentiation of osteoblasts as well. Thus, receptors for these cytokines are expressed on a variety of stromal/osteoblastic cells, and ligand binding induces progression toward a more mature osteoblast phenotype, characterized by increased alkaline phosphatase and osteocalcin expression, and a concomitant decrease in proliferation (53 54 ). Moreover, IL-6 type cytokines stimulate the development of osteoblasts from noncommitted embryonic fibroblasts obtained from 12-day-old murine fetuses (55 ). Consistent with the in vitro evidence, several in vivo studies have demonstrated increased bone formation in transgenic mice overexpressing OSM or LIF (56 57 ).
TGFß is another example of a factor affecting both bone formation and bone resorption (58 ). Thus, in addition to its ability to stimulate osteoblast differentiation, TGFß increases bone resorption by stimulating osteoclast formation. Injection of TGFß into the subcutaneous tissue that overlies the calvaria of adult mice causes increased bone resorption accompanied by the development of unusually large osteoclasts, as well as increased bone formation. The effects of TGFß might be mediated by other cytokines involved in osteoclastogenesis as TGFß can stimulate their production. Mice lacking the TGFß1 gene due to targeted disruption exhibit excessive production of inflammatory cells, suggesting that this growth factor normally operates to suppress hematopoiesis (59 ).
C. Systemic hormones
The two principal hormones of the calcium homeostatic system,
namely PTH and l,25-dihydroxyvitamin D3
[1,25-(OH)2D3], are
potent stimulators of osteoclast formation (17 60 ). The ability of
these hormones to stimulate osteoclast development and to regulate
calcium absorption and excretion from the intestine and kidney,
respectively, are the key elements of extracellular calcium
homeostasis. Calcitonin, the third of the classical bone-regulating
hormones, inhibits osteoclast development and activity and promotes
osteoclast apoptosis. Although the antiresorptive properties of
calcitonin have been exploited in the management of bone diseases with
increased resorption, the role of this hormone in bone physiology in
humans, if any, remains questionable (61 62 63 ). PTH, PTH-related
peptide, and 1,25-(OH)2D3
stimulate the production of IL-6 and IL-11 by stromal/osteoblastic
cells (49 64 65 66 ). Several other hormones, including estrogen,
androgen, glucocorticoids, and T4, exert potent
regulatory influences on the development of osteoclasts and osteoblasts
by regulating the production and/or action of several cytokines (21 64 67 68 69 ).
D. Adhesion molecules
In addition to autocrine, paracrine, and endocrine signals,
cell-cell and cell-matrix interactions are also required for the
development of osteoclasts and osteoblasts (70 71 72 ). Such interactions
are mediated by proteins expressed on the surface of these cells and
are responsible for contact between osteoclast precursors with
stromal/osteoblastic cells and facilitation of the action of paracrine
factors anchored to the surface of cells that are required for bone
cell development. Adhesion molecules are also involved in the migration
of osteoblast and osteoclast progenitors from the bone marrow to sites
of bone remodeling as well as the cellular polarization of osteoclasts
and the initiation and cessation of osteoclastic bone resorption. More
important, for the purpose of this review, adhesion molecules play a
role in the control of osteoblast and osteoclast development and
apoptosis (73 74 75 76 77 ).
The list of adhesion molecules that influence bone cell development and
function includes the integrins, particularly
vß3 and
2ß1, selectins, and
cadherins, as well as a family of transmembrane proteins containing a
disintegrin and metalloprotease domain (ADAMS). Each of these proteins
recognizes distinct ligands. For example, some integrins recognize a
specific amino acid sequence (RGD) present in collagen, fibronectin,
osteopontin, thrombospondin, bone sialoprotein, and vitronectin (78 ).
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IV. Reciprocal Relationship Between Osteoblastogenesis and Adipogenesis |
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It is likely that interconversion of stromal cells among phenotypes, as
well as commitment to a particular lineage with suppression of
alternative phenotypes, is governed by specific transcription factors.
Indeed, Cbfa1 is required for commitment of mesenchymal progenitors to
the osteoblast lineage. Mice that are deficient in this factor lack
osteoblasts and mineralized bone matrix (26 ); and expression of Cbfa1
in fibroblastic cells induces transcription of osteoblast- specific
genes (24 ). On the other hand, CCAAT/enhancer binding protein
(C/EBP), C/EBPß, and C/EBP
, as well as peroxisome proliferator
activated receptor 1 (PPAR1) and PPAR2 orchestrate adipocyte
differentiation (87 88 89 90 ). Introduction of C/EBP in fibroblastic
cells induces adipocyte differentiation (91 92 ), and transfection of
fibroblastic cells with PPAR2 and subsequent activation with an
appropriate ligand causes the development of adipocytes (93 ).
Using clonal cell lines isolated from the murine bone marrow, it has
been demonstrated that PPAR2 can convert stromal cells from a
plastic osteoblastic phenotype that reversibly expresses adipocyte
characteristics to terminally differentiated adipocytes. Moreover,
PPAR2 suppresses the expression of Cbfa1 and thereby
osteoblast-specific genes (94 ). Similar to the inhibitory effect of
PPAR2 on the osteoblast phenotype, the combination of PPAR and
C/EBP suppresses the muscle cell phenotype when transfected into G8
myoblastic cells (95 ). Taken together, these findings strongly suggest
that PPAR2 plays a hierarchically dominant role in the determination
of the fate of mesenchymal progenitors, due to its ability to inhibit
the expression of other lineage-specific transcription factors. Studies
with a clonal cell line (2T3) suggest that BMP-2 induces osteoblast or
adipocyte differentiation in mesenchymal precursors, depending on
whether the BMP receptor type IA or IB is activated. Therefore, BMP
receptors may also play a critical role in both the specification and
reciprocal differentiation of osteoblast and adipocyte progenitors
(96 ).
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V. Serial and Parallel Models of Osteoblast and Osteoclast Development |
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As the BMU advances, cells are successively recruited at each new
cross-sectional location. Osteoblasts do not arrive until the
osteoclasts have moved on. However, during the longitudinal progression
of the BMU as a whole, new osteoclasts and new osteoblasts are needed
simultaneously, although not at the same location. Two models of
osteoblast recruitment, a serial and a parallel (Fig. 1), can explain the distinction between
the cross-sectional and longitudinal events during BMU progression
(38 ). According to the serial model, factors released from resorbed
bone or the local increase in mechanical strain resulting from
bone resorption, stimulate osteoblast precursor cell proliferation and
differentiation (98 99 100 ). According to the parallel model, osteoblast
and osteoclast precursor proliferation and differentiation occur
concurrently in response to whatever signal conveys the need for
initiation of new BMUs, and whatever hormone prolongs their progression
(10 38 ). With either model, new osteoblasts must be directed to the
right location.
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In full agreement with the in vitro evidence for the dependency of osteoclast development on support by cells related to osteoblasts, mice lacking osteoblasts due to Cbfa1 deficiency also lack osteoclasts (26 ). In addition, marrow cells from SAMP6 mice, a strain with defective osteoblastogenesis, exhibit decreased osteoclastogenesis (105 ) and do not exhibit the expected increase in osteoclastogenesis nor do they lose bone after loss of sex steroids (106 ).
The molecular mechanism of the dependency of osteoclastogenesis on
cells of the mesenchymal lineage has been elucidated during the last 2
yr with the discovery of three proteins involved in the TNF signaling
pathway (reviewed in Ref. 107 ). Two of these proteins are
membrane-bound cytokine-like molecules: the receptor activator of
nuclear factor-
B (NF-B) (RANK) and the RANK-ligand. Other names
used in the literature for RANK are osteoprotegerin ligand (OPG-L) and
TRANCE. RANK is expressed in hematopoietic osteoclast progenitors,
while RANK-ligand is expressed in committed preosteoblastic cells and T
lymphocytes (108 109 110 ). RANK-ligand binds to RANK with high affinity.
This interaction is essential and, together with M-CSF, sufficient for
osteoclastogenesis.
1,25-(OH)2D3, PTH, PTHrP,
gp130 activating cytokines (e.g., IL-6, IL-11), and IL-1
induce the expression of the RANK-ligand in stromal/osteoblastic cells
(50 107 ). Osteoprotegerin (OPG), the third of the three proteins,
unlike the other two, is a secreted disulfide-linked dimeric
glycoprotein. A hydrophobic leader peptide and three and one-half TNF
receptor-like cysteine-rich pseudorepeats characterize the amino
terminus of this protein. Unlike other members of the TNF receptor
family, OPG does not posses a transmembrane domain. OPG has very potent
inhibitory effects on osteoclastogenesis and bone resorption in
vitro and in vivo (111 ). Consistent with an important
role of OPG in the regulation of osteoclast formation, OPG transgenic
mice develop osteopetrosis, whereas OPG knockout mice exhibit severe
osteoporosis (112 ). The antiosteoclastogenic property of OPG is due to
its ability to act as a decoy by binding to RANK-ligand and blocking
the RANK-ligand/RANK interaction. In addition to skeletal metabolism,
the RANK/RANK-ligand/OPG circuit may regulate several other biological
systems. Indeed, OPG is produced by many tissues other than bone,
including skin, liver, stomach, intestine, lung, heart, kidney, and
placenta as well as hematopoietic and immune organs. Consistent with
this, mice deficient in RANK-ligand completely lacked lymph nodes as
well as osteoclasts (113 ). Moreover, OPG is also a receptor for the
cytotoxic ligand TRAIL (TNF-related apoptosis-inducing ligand) to which
it binds with high affinity and inhibits TRAIL-mediated apoptosis in
lymphocytes (114 ) and also regulates antigen presentation and T cell
activation (115 ).
Osteoblastic cells and T lymphocytes, the two cell types that express
high levels of RANK-ligand, are also the two cell types that express
high levels of the osteoblast-specific transcription factor Cbfa1 (24 ).
More intriguingly, both the murine and human RANK-ligand genes contain
two functional Cbfa1 sites, and mutation of these sites abrogates the
transcriptional activity of the RANK-ligand gene promoter (116 ).
Therefore, the cell-specific expression of RANK-ligand in cells of the
stromal/osteoblastic lineage and concurrent differentiation of
osteoblasts and osteoclasts might be dictated, at least in part, by
interaction between an osteoblast-specific transcription factor and
RANK-ligand. BMP 2 and -4 stimulate Cbfa1 expression. Based on these
lines of evidence, it has been postulated that the molecular
underpinnings of the control of the rate of bone regeneration and the
concurrent production of osteoclasts and osteoblasts could well be a
BMP
Cbfa1RANK-ligand
gene expression cascade in cells of the bone marrow
stromal/osteoblastic lineage (117 118 ). According to this hypothesis,
BMPs may provide the tonic baseline control of both processes, and
thereby the rate of bone remodeling, upon which other inputs
(e.g., biomechanical, hormonal, etc.) operate.
Studies with transgenic and knockout animal models as well as models
with spontaneous genetic mutations have identified at least three
transcription factors that are required for osteoclast differentiation:
PU-1, fos, and NF-b. A review of the precise role of these factors
is beyond the scope of this article, but the reader is referred to a
recent excellent review of the topic (119 ).
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VI. Function of the Mature Cells |
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In addition to being the cells that produce the osteoid matrix, mature osteoblasts are essential for its mineralization, the process of deposition of hydroxyapatite (123 124 ). Osteoblasts are thought to regulate the local concentrations of calcium and phosphate in such a way as to promote the formation of hydroxyapatite. In view of the highly ordered, well aligned, collagen fibrils complexed with the noncollagenous proteins formed by the osteoblast in lamellar bone, it is likely that mineralization proceeds in association with, and perhaps governed by, the heteropolymeric matrix fibrils themselves. Osteoblasts express relatively high amounts of alkaline phosphatase, which is anchored to the external surface of the plasma membrane. Alkaline phosphatase has been long thought to play a role in bone mineralization. Consistent with this, deficiency of alkaline phosphatase due to genetic defects leads to hypophosphatasia, a condition characterized by defective bone mineralization (125 ). However, the precise mechanism of mineralization and the exact role of alkaline phosphatase in this process remain unclear. Bone mineralization lags behind matrix production and, in remodeling sites in the adult bone, occurs at a distance of 8–10 µm from the osteoblast. Matrix synthesis determines the volume of bone but not its density. Mineralization of the matrix increases the density of bone by displacing water, but does not alter its volume.
B. Osteocytes
Some osteoblasts are eventually buried within lacunae of
mineralized matrix. These cells are termed osteocytes and are
characterized by a striking stellate morphology, reminiscent of the
dendritic network of the nervous system (126 127 ). Osteocytes are the
most abundant cell type in bone: there are 10 times as many osteocytes
as osteoblasts. Osteocytes are regularly spaced throughout the
mineralized matrix and communicate with each other and with cells on
the bone surface via multiple extensions of their plasma membrane that
run along the canaliculi; osteoblasts, in turn, communicate with cells
of the bone marrow stroma which extend cellular projections onto
endothelial cells inside the sinusoids. Thus, a syncytium extends from
the entombed osteocytes all the way to the vessel wall (128 ) (Fig. 2). As a consequence, the strategic
location of osteocytes makes them excellent candidates for
mechanosensory cells able to detect the need for bone augmentation or
reduction during functional adaptation of the skeleton, and the need
for repair of microdamage, and in both cases to transmit signals
leading to the appropriate response; albeit this remains hypothetical
(129 ). Osteocytes evidently sense changes in interstitial fluid flow
through canaliculi (produced by mechanical forces) and detect changes
in the levels of hormones, such as estrogen and glucocorticoids, that
influence their survival and that circulate in the same fluid
(130 131 132 ). Therefore, disruption of the osteocyte network is likely to
increase bone fragility.
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D. Osteoclasts
Mature osteoclasts are usually large (50 to 100 µm diameter)
multinucleated cells with abundant mitochondria, numerous lysosomes,
and free ribosomes. Their most remarkable morphological feature is the
ruffled border, a complex system of finger-shaped projections of the
membrane, the function of which is to mediate the resorption of the
calcified bone matrix (17 123 ). This structure is completely
surrounded by another specialized area, called the clear zone. The
cytoplasm in the clear zone area has a uniform appearance and contains
bundles of actin-like filaments. The clear zone delineates the area of
attachment of the osteoclast to the bone surface and seals off a
distinct area of the bone surface that lies immediately underneath the
osteoclast and which eventually will be excavated. The ability of the
clear zone to seal off this area of bone surface allows the formation
of a microenvironment suitable for the operation of the resorptive
apparatus.
The mineral component of the matrix is dissolved in the acidic environment of the resorption site, which is created by the action of an ATP-driven proton pump (the so-called vacuolar H+-ATPase) located in the ruffled border membrane. The protein components of the matrix, mainly collagen, are degraded by matrix metalloproteinases, and ca-thepsins K, B, and L are secreted by the osteoclast into the area of bone resorption (134 ). The degraded bone matrix components are endocytosed along the ruffled border within the resorption lacunae and then transcytosed to the membrane area opposite the bone, where they are released (135 136 ). Another feature of osteoclasts is the presence of high amounts of the phosphohydrolase enzyme, tartrate-resistant acid phosphatase (TRAPase). This feature is commonly used for the detection of osteoclasts in bone specimens (137 ). Mice deficient in TRAPase exhibit a mild osteopetrotic phenotype (due to an intrinsic defect of osteoclastic resorptive activity) and defective mineralization of the cartilage in developing bones (138 ).
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VII. Death of Bone Cells by Apoptosis |
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). After
osteoclasts have eroded to a particular distance, either from the
central axis in cortical bone or to a particular depth from the surface
in cancellous bone, they die and are quickly removed by phagocytes
(139 ). The majority (65%) of the osteoblasts that originally assembled
at the remodeling site also die (140 ). The remaining are converted to
lining cells that cover quiescent bone surfaces or are entombed within
the mineralized matrix as osteocytes (Fig. 3A). Both osteoclasts and osteoblasts die
by apoptosis, or programmed cell death, a process common to several
regenerating tissues (141 ). As in other tissues, bone cells undergoing
apoptosis are recognized by condensation of chromatin, the degradation
of DNA into oligonucleosome-sized fragments, and the formation of
plasma and nuclear membrane blebs (Fig. 4). Eventually the cell breaks apart to
form so-called apoptotic bodies. Osteoblast apoptosis explains the fact
that 50–70% of the osteoblasts initially present at the remodeling
site of human bone cannot be accounted for after enumeration of lining
cells and osteocytes (142 ). Moreover, the frequency of osteoblast
apoptosis in vivo is such that changes in its timing and
extent could have a significant impact in the number of osteoblasts
present at the site of bone formation (130 ). Osteocytes are long-lived
but not immortal cells; some die by apoptosis (132 143 144 ).
Osteocyte apoptosis could be of importance to the origination and/or
progression of the BMU. Indeed, osteocytes are the only cells in bone
that can sense the need for remodeling at a specific time and
place. Moreover, osteocytes are in direct physical contact with
lining cells on the bone surface, and targeting of osteoclast
precursors to a specific location on bone depends on a "homing"
signal given by lining cells (133 ).
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VIII. Regulation of Bone Cell Proliferation and Activity |
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In regenerating tissues, the initial commitment of a stem cell progeny is followed by amplification with several or many rounds of cell division. In most tissues, division of stem cells is infrequent, and almost all of the divisions that produce the final population of differentiated cells occur in the so-called transit compartment (152 ). This notion is obscured by the frequent practice of showing linear diagrams representing the transition from one cell type to another and ignoring completely the amplification during the transition. In general, terminally differentiated cells do not divide, and an osteoblast, defined as a cell making bone matrix, and osteoclast, as a cell resorbing bone, are in this category. Therefore, the in vivo relevance of much of the in vitro evidence on the regulation of osteoblastic or osteoclastic cell proliferation, using established cell lines or primary cultures of isolated cells, must be largely confined to changes in this transit compartment. Irrespective of whether a given regulatory factor, be that a cytokine or a hormone, influences the initial commitment of a stem cell, or the subsequent amplification of its progeny, or both, the end result is a change in the rate of production and therefore the number of cells available for the execution of the biological task. For the sake of simplicity, the terms birth, rate of birth, osteoblastogenesis, or osteoclastogenesis, as used in this article, implicitly combine commitment and amplification.
The in vivo relevance of numerous reports of in vitro observations of changes in the biosynthetic activity of osteoblastic cells, e.g., changes in the level of expression of osteocalcin or alkaline phosphatase in response to a given agent, is also a matter of conjecture. Most likely, given the nature of commonly used in vitro cell models which, by and large, represent preterminally differentiated cells, such observations might be more relevant to postcommitment differentiation events, than to altered activity of the fully differentiated cell. Moreover, even if some agents can alter the function of terminally differentiated cells in short-term cultures in vitro, heretofore there is no evidence that short-term change in the rate of collagen production or bone matrix digestion, for example, are ultimately translated into differences in the amounts of bone matrix formed or resorbed.
In the bone literature there is considerable ambiguity when using the term "activation." It is important that one distinguishes between activation as a switch from an off state to an on state, and activation as modulation of activity of an already active cell. Morphological evidence summarized elsewhere does not support the notion that completely inactive osteoclasts are waiting for a stimulus to make them active (117 ). However, this evidence does not address the issue of whether there are variations in the rate of bone matrix dissolution by individual osteoclasts after they started work.
Studies with the widely used bone slice pit bioassay have shown that several regulatory factors can cause a decrease or increase in the resorptive ability of individual osteoclasts (153 154 155 ). However, it is not clear to what extent these observations reflect a change in cell vigor as opposed to a change in the precariously short lifespan of osteoclasts in vitro. In estrogen deficiency, individual osteoclasts are seemingly more "active" as they dig deeper resorption cavities often leading to trabecular perforation, but it has been convincingly argued that this is due to delayed apoptosis (133 ). In Paget’s disease osteoclasts are certainly far more aggressive than normal, perhaps as a result of their uniquely large size and number of nuclei (156 ). Today, the most compelling evidence in support of the notion that the vigor of individual osteoclasts may not always be maximal comes from in vitro as well as in vivo experiments with soluble RANK-ligand (157 ). Specifically, it has been found that RANK-ligand acts on mature rat osteoclasts in vitro to stimulate more frequent cycles of resorption and induce rearrangements of the cytoskeleton. Moreover, intravenous administration of RANK-ligand to mice elevates the circulating concentration of ionized calcium within 1 h. RANK-ligand has potent antiapoptotic effects on cultured osteoclasts (Ref. 158 and William Boyle, personal communication). Therefore, definitive conclusions regarding RANK-ligand’s ability to modulate osteoclast vigor will have to await dissection of the contribution of its effects on osteoclast survival in vivo. Similar to osteoclasts, the bone-forming ability of osteoblasts may not be always maximal, as suggested by the evidence that PTH can rapidly enhance bone formation when administered by subcutaneous injections to rats (159 ).
To conclude this section, it is intuitive that the amount of bone resorbed or formed by a team of osteoclasts and osteoblasts should be a function of the total cell number as well as the vigor of individual cells. However, whereas cell number can be quantified on bone sections from animals and humans with conventional histomorphometric techniques, quantification of individual cell vigor cannot. This situation makes it difficult to judge at present whether cell vigor is or is not a critical component in the pathogenesis of abnormal skeletal regeneration in common acquired metabolic bone diseases such as postmenopausal, senile, or steroid-induced osteoporosis. For this reason and space limitations, changes in bone cell vigor or other potential mechanisms of osteoporosis resulting from changes in extraskeletal tissues, for example altered calcium absorption or excretion, will not be discussed in the following section. This also reflects the author’s intention to focus on the dynamics of bone cell number, rather than a dismissal of other mechanisms.
|
IX. Pathogenesis Of Osteoporosis |
|---|
).
|
and gp130, in cells of the bone marrow
stromal/osteoblastic lineage (40 163 ). Suppression of IL-6 production
by estrogen or selective estrogen receptor modulators (SERMs), such as
raloxifene, does not require direct binding of the estrogen receptor to
DNA. Instead, it is due to protein-protein interaction between the
estrogen receptor and transcription factors such as NF-Kß and C/EBP.
This mechanism provides a model that best fits current understanding of
the molecular pharmacology of estrogen and SERMs (164 ). Consistent with
the suppressive effect of sex steroids on IL-6 and its receptor,
several, albeit not all, studies have shown that the level of
expression of IL-6, as well as IL-6R and gp130, is elevated in
estrogen-deficient mice and rats as well as in humans, in the bone
marrow and in the peripheral blood (165 166 167 168 ). Furthermore,
neutralization of IL-6 with antibodies or knockout of the IL-6 gene in
mice prevents the expected cellular changes in the marrow and in
trabecular bone sections and protects the mice from bone loss after
loss of sex steroids (51 67 ). Consistent with its pathogenetic role in
the bone loss caused by loss of sex steroids, IL-6 seems to play a
similar role in several other conditions associated with increased bone
resorption as evidenced by increased local or systemic production of
IL-6 and the IL-6 receptor in patients with multiple myeloma, Paget’s
disease, rheumatoid arthritis, Gorham-Stout or disappearing bone
disease, hyperthyroidism, primary and secondary hyperparathyroidism, as
well as McCune Albright Syndrome (66 68 169 170 171 172 173 174 ). In line with the fact that loss of sex steroids increases the rate of bone remodeling, in addition to up-regulating osteoclastogenesis, loss of sex steroids increases the number of osteoblast progenitors in the murine bone marrow. These changes are temporally associated with increased bone formation and parallel the increased osteoclastogenesis and bone resorption (175 ). As IL-6 type cytokines can stimulate osteoblast development and differentiation (54 55 146 ), increased sensitivity to IL-6 and other members of this cytokine’s family may account also for the increased osteoblast formation that follows the loss of gonadal function. In view of the fact that mesenchymal cell differentiation and osteoclastogenesis are tightly linked, stimulation of mesenchymal cell differentiation toward the osteoblastic lineage after sex steroid loss may be the first event that ensues after the hormonal change, and increased osteoclastogenesis and bone loss might be downstream consequences of this change (106 ).
In addition to IL-6, estrogen also suppress TNF and M-CSF (176 177 ), and estrogen loss may increase the sensitivity of osteoclasts to IL-1 by increasing the ratio of the IL-1RI over the IL-1 receptor antagonist (IL-RII) (178 ). As in the case of IL-6, the effects of estrogen on TNF and M-CSF are mediated via protein-protein interactions between the estrogen receptor and other transcription factors. In agreement with the evidence that IL-1 and TNF play a role in the bone loss caused by loss of estrogen, administration of IL-1RA and/or a TNF soluble receptor ameliorates the bone loss caused by ovariectomy in rats and mice (179 180 181 ). Because of the interdependent nature of the production of IL-1, IL-6, and TNF, a significant increase in one of them may amplify, in a cascade fashion, the effect of the others (161 ). Interestingly, recent in vitro studies with human osteoblastic cells indicate that OPG production is stimulated by estrogen, suggesting that this cytokine may also play an important role in the antiosteoclastogenic (antiresorptive) action of estrogen on bone (182 ).
Increased remodeling, resulting from up-regulation of osteoblastogenesis and osteoclastogenesis, alone can cause a transient acceleration of bone mineral loss because bone resorption is faster than bone formation, and new bone is less dense than older bone. However, in addition to increased bone remodeling, loss of sex steroids leads to a qualitative abnormality: osteoclasts erode deeper than normal cavities (133 183 ). In this manner, sex steroid deficiency leads to the removal of some cancellous elements entirely; the remainder are more widely separated and less well connected. An equivalent amount of cancellous bone distributed as widely separated, disconnected, thick trabeculae is biomechanically less competent than when arranged as more numerous, connected, thin trabeculae. Concurrent loss of cortical bone occurs by enlargement and coalescence of subendocortical spaces, a process due to deeper penetration of endocortical osteoclasts.
This deeper erosion can be now explained by evidence that estrogen acts on mature osteoclasts to promote their apoptosis; consequently, loss of estrogen leads to prolongation of the lifespan of osteoclasts (133 ). Specifically, estrogen promotes osteoclast apoptosis in vitro and in vivo by 2- to 3-fold, an effect seemingly mediated by TGFß (139 ). In direct contrast to their proapoptotic effects on osteoclasts, estrogen (as well as androgen) exerts antiapoptotic effects on osteoblasts and osteocytes; consequently, loss of estrogen or androgen leads to shorter lifespan of osteoblasts and osteocytes (184 ). Extension of the working life of the bone-resorbing cells and simultaneous shortening of the working life of the bone-forming cells, can explain the imbalance between bone resorption and formation that ensues after loss of sex steroids. Furthermore, the increase in osteocyte apoptosis could further weaken the skeleton by impairment of the osteocyte-canalicular mechanosensory network. The increase in bone remodeling that occurs with estrogen deficiency would partly replace some of the nonviable osteocytes in cancellous bone, but cortical apoptotic osteocytes might accumulate because of their anatomic isolation from scavenger cells and the need for extensive degradation to small molecules to dispose of the osteocytes through the narrow canaliculi. Hence, the accumulation of apoptotic osteocytes caused by loss of estrogen, or glucocorticoid excess (130 ), could increase bone fragility even before significant loss of bone mass, because of the impaired detection of microdamage and repair of substandard bone.
In conclusion, the increased rate of bone remodeling in estrogen deficiency may be due to increased production of both osteoclasts and osteoblasts, and the imbalance between bone resorption and formation is due to an extension of the working lifespan of the osteoclast and shortening of the working lifespan of the osteoblast. Moreover, a delay of osteoclast apoptosis seems responsible for the deeper resorption cavities and thereby the trabecular perforation associated with estrogen deficiency.
Clinical observations of decreased bone mass in a male with mutant estrogen receptor (185 ), and increased bone mass after treatment with estrogen in two males with P-450 aromatase deficiency (186 187 ), have raised the possibility that estrogen derived by peripheral aromatization of androgens is critical for the maintenance of bone mass in men as well as in women (188 ). However, in all three cases, the decreased bone mass in young males with estrogen deficiency in the face of androgen sufficiency could be due to failure in achieving peak bone mass from defects occurring during development or growth, not to loss of bone mass, as it is the case with common forms of osteoporosis. In addition, individuals with complete androgen insensitivity, due to mutations in the androgen receptor gene on the X chromosome and increased testosterone and estrogen production, have decreased bone mass, in spite of the elevated estrogen levels (189 ). Moreover, androgens, including nonaromatizable ones, have identical effects to those of estrogen on the biosynthetic activity and the birth as well as the death of bone cells in vitro and in vivo, at least in rodents (67 106 190 ). It is therefore more likely that both estrogen and androgen are important for the maintenance of bone mass in the adult male skeleton.
B. Senescence
The amount of bone formed during each remodeling cycle decreases
with age in both sexes. This is indicated by a consistent histological
feature of the osteopenia that occurs during aging, namely a decrease
in wall thickness, especially in trabecular bone (191 192 193 ). Wall
thickness is a measure of the amount of bone formed in a remodeling
packet of cells and is determined by the number or activity of
osteoblasts at the remodeling site.
Studies measuring bone turnover by histomorphometry (194 ), or indirectly by circulating markers (195 196 197 ), have suggested that in aging women, even in extreme old age, bone turnover is most likely increased by secondary hyperparathyroidism or by the continuing effect of estrogen deficiency. Increased turnover and reduced wall thickness are not inconsistent, as the former is the result of increased activation frequency, and the decreased wall thickness—an index of decreased bone formation by osteoblasts—in senescence is local and relative to the demand created by resorption.
Changes in the birth of bone cells in the bone marrow provide a
mechanistic explanation for the contribution of senescence to bone
loss, independently from sex steroid deficiency. Specifically, using
SAMP6 mice, a murine model of age-related osteopenia (but sufficient in
sex steroids and with intact reproductive function), a tight
association among reduced number of osteoblast progenitors, decreased
bone formation, and decreased bone mass has been established (105 ).
Decreased osteoblastogenesis with advancing age has been confirmed in
the human bone marrow (198 199 ). Importantly, the decrease in
osteoblastogenesis is accompanied by increased adipogenesis and
myelopoiesis, as well as decreased osteoclastogenesis, the latter most
likely caused by a reduction in the stromal/osteoblastic cells that
support osteoclast formation (105 200 ). This suggests that in aging
there must be changes in the expression of genes that favor the
differentiation of multipotent mesenchymal stem cells toward adipocytes
at the expense of osteoblasts. The evidence that PPAR2 induces the
terminal differentiation of marrow cells with both osteoblastic and
adipocytic characteristics to adipocytes, and simultaneously suppresses
Cbfa1 expression and terminal differentiation to osteoblasts (94 ),
raises the possibility that increased expression of PPAR2 or its
ligands, e.g., PGJ2, may be some of the culprits responsible
for the reciprocal change between adipogenesis and
osteoblastogenesis with advancing age (Table 2).
Uptake of oxidized low-density lipoproteins (LDL) play an important
role in foam cell formation and the pathogenesis of atherosclerosis.
Two of the major components of oxidized LDL,
9-hydroxy-9,11-octadecadienoic acid (HODE) and 13-HODE, are
endogenous ligands and activators of PPAR (201 ), and PPAR
promotes monocyte/macrophage differentiation and uptake of oxidized LDL
(202 ). Taken together with these findings, the evidence that activated
PPAR2 promotes adipocyte differentiation at the expense of
osteoblastogenesis in the bone marrow by suppressing Cbfa1 (94 )
suggests a mechanistic link among dietary fat/lipoproteins, bone marrow
stromal cell differentiation, osteoporosis, and atherogenesis. In
support of the existence of such a link, activation of PPAR by
thiazolidinediones or oxidatively modified LDL inhibits
osteoblastogenesis of bone marrow-derived stromal cells in
vitro (94 203 204 ). Moreover, high fatty acid content in rabbit
serum or high fat diet of mice for 4 months decreases osteogenic cell
differentiation in ex vivo bone marrow cell cultures (86 204 ). These new advances may explain clinical observations that
atherosclerosis and osteoporosis coexist (205 206 ).
Quantitative trait loci (QTLs) analysis of osteopenia-associated loci
using closely related mouse strains have mapped five loci to regions of
chromosomes 2, 7, 11, and 16 (207 ). Association of these same loci with
bone mineral density has been reproduced in crosses of different
recombinant-inbred mouse strains (208 209 ). Such recurrent appearance
of QTL, especially in crosses involving distantly related strains,
implies that polymorphism at these loci may be favored by evolution and
might underlie variation in peak bone density among humans.
Intriguingly, of the more than 12 genes affecting bone homeostasis that
were localized near these QTLs, 2 are prostaglandin synthases, a third
is the BMP-2/4 antagonist noggin, a fourth is the proapoptotic protein
bax, and the fifth is IL-11. Hence, the transcription factor PPAR2
and its ligand, PGJ2, noggin, and IL-11 are potentially responsible for
the decreased osteoblastogenesis with advancing age. This contention is
supported by the evidence that the reciprocal relationship between
decreased osteoblastogenesis and increased adipogenesis in the SAMP6
mouse may be explained by a change in the expression of PPAR or its
ligands in early mesenchymal progenitors; that BMP-2/4, in balance with
noggin, may determine the tonic baseline control of the rate of
osteoblastogenesis; and that IL-11 is a potent inhibitor of
adipogenesis, which stimulates osteoblast differentiation and the
expression of which is reduced in SAMP6 mice. In addition to
these factors, growth factors such as IGFs have also been implicated in
the bone loss associated with senescence (210 211 ). Irrespective of
the identity of the precise mediator, the reciprocal change between
adipogenesis and osteoblastogenesis can explain the association of
decreased relative bone formation and the resulting osteopenia with the
increased adiposity of the marrow seen with advancing age in animals
and humans (105 142 212 213 214 215 ).
C. Glucocorticoid excess
The cardinal histological features of glucocorticoid-induced
osteoporosis are decreased bone formation rate, decreased wall
thickness of trabeculae (a strong indication of decreased work output
by osteoblasts), and in situ death of portions of bone.
Increased bone resorption, decreased osteoblast proliferation and
biosynthetic activity, and sex-steroid deficiency, as well as
hyperparathyroidism resulting from decreased intestinal calcium
absorption and hypercalciuria due to defective vitamin D metabolism,
have all been proposed as mechanisms for the loss of bone that ensues
with glucocorticoid excess (216 ).
The decreased bone formation and osteonecrosis can now be explained by
evidence that glucocorticoid excess has a suppressive effect on
osteoblastogenesis in the bone marrow and also promotes the apoptosis
of osteoblasts and osteocytes (118 ). Indeed, mice receiving
glucocorticoids for 4 weeks, a period equivalent to 
3–4 yr in
humans, exhibit decreased bone mineral density associated with a
decrease in the number of osteoblast, as well as osteoclast,
progenitors in the bone marrow and a dramatic reduction in cancellous
bone area and in trabecular width compared with placebo controls. These
changes are associated with a significant reduction in osteoid area and
a decrease in the rates of mineral apposition and bone formation. More
strikingly, glucocorticoid administration to mice causes a 3-fold
increase in the prevalence of osteoblast apoptosis in vertebrae and
induced apoptosis in 28% of the osteocytes in metaphyseal cortical
bone. Nevertheless, even though there is a significant correlation
between the severity of the bone loss and the extent of reduction in
bone formation, some of the bone loss may be due to an early increase
in bone resorption as evidenced by an early increase in osteoclast
perimeter of vertebral cancellous bone after 7 days of steroid
treatment. In vivo studies with mice from this author’s
group show that at this early time point (7 days after glucocorticoid
administration) osteoclastogenesis in ex vivo bone marrow
cultures is decreased by half, while the number of osteoclasts in bone
sections doubles (Robert Weinstein, personal communication), suggesting
that an early effect of glucocorticoid excess might be increased
osteoclast survival. In vitro studies by others, on the
other hand, have shown that glucocorticoids inhibit OPG and
concurrently stimulate the expression of RANK-ligand in human
osteoblastic, primary, and immortalized bone marrow stromal cells
(217 ). Taken together, these lines of evidence suggest that the initial
rapid phase of bone loss with glucocorticoid treatment could be due to
an extension of the lifespan of preexisting osteoclasts, mediated by
RANK- ligand (117 ).
The same histomorphometric changes that have been found in mice after a 4-week treatment with steroids have been confirmed in biopsies from patients receiving long-term glucocorticoid therapy. Moreover, as in mice, an increase in osteoblast and osteocyte apoptosis is found in human biopsies. Compared with osteoblast apoptosis, apoptotic osteocytes are far more prevalent, at least in metaphyseal cortices, probably because of the anatomical isolation of osteocytes from scavenger cells. Consistent with these findings, glucocorticoids promote osteoblast and osteocyte apoptosis in vitro (218 219 ). Decreased production of osteoclasts can explain the reduction in bone turnover with chronic glucocorticoid excess, whereas decreased production and apoptosis of osteoblasts can explain the decline in bone formation and trabecular width. Accumulation of apoptotic osteocytes may also explain the so-called "osteonecrosis," also known as aseptic or avascular necrosis, another manifestation of steroid-induced osteoporosis that causes collapse of the femoral head in as many as 25% of patients (220 ). This contention is supported by evidence that whole femoral heads obtained from patients with glucocorticoid-induced osteoporosis exhibit abundant apoptotic osteocytes adjacent to the subchondral fracture crescent (221 ). Glucocorticoid-induced osteocyte apoptosis, a cumulative and unrepairable defect, could uniquely disrupt the proposed mechanosensory role of the osteocyte network and thus promote collapse of the femoral head.
At this time, the mediators of the cellular changes caused by
glucocorticoid excess are only a matter of conjecture. Nonetheless,
glucocorticoids directly suppress BMP-2 and Cbfa1-2—two critical
factors for osteoblastogenesis—and may also decrease the production of
IGFs while they stimulate the transcriptional activity of PPAR2
(222 223 224 225 ) (Table 2).
|
X. Pharmacotherapeutic Implications of Osteoblast and Osteocyte Apoptosis |
|---|
A. Intermittent PTH administration
The ideal therapy for osteoporosis, especially in elderly patients
who already have advanced bone loss, would be an anabolic agent that
will increase bone mass by rebuilding bone. It is well established that
daily injections of low doses of PTH—an agent better known for its
role in calcium homeostasis—increases bone mass in animals and humans
(226 227 228 229 230 231 ) as does the PTH-related protein (PTHrP), the only other
known ligand of the PTH receptor (232 ). Indeed, although constant, high
levels of PTH cause increased bone resorption and osteitis fibrosa
cystica, low and intermittent doses of PTH, too small to affect serum
calcium concentrations, promote bone formation and increase bone
mineral density at the lumbar spine and hip. This so-called anabolic
effect can be now explained by evidence that PTH increases the life
span of mature osteoblasts in vivo by reducing the
prevalence of their apoptosis from 1.7–2.2% to as little as
0.1–0.4% rather than by affecting the generation of new
osteoblasts (218 ). The antiapoptotic effect of PTH in mice was
sufficient to account for the increase in bone mass and was confirmed
in vitro using rodent and human osteoblasts and osteocytes.
Like PTH, PGE inhibits periosteal cell apoptosis via cAMP-dependent
stimulation of sphingosine kinase (233 ). Interestingly, whereas PTH
inhibits apoptosis in cells overexpressing Gs, an activator of
adenylate cyclase, PTH stimulates apoptosis via G protein-coupled
receptors in cells overexpressing Gq (an activator of JNK and calcium
signaling), suggesting that the antiapoptotic effects of PTH are
mediated by signals transduced through the Gs pathway (234 ).
Osteocytes in the newly made lamellar cancellous bone in the mice
receiving daily PTH injections were closer together and more numerous
than those found in the animals receiving vehicle alone (218 ). The
closely spaced, more numerous osteocytes are the predictable
consequence of protecting osteoblasts from apoptosis (Fig. 3B). The
antiapoptotic effect of PTH on osteoblasts as well as osteocytes has
been confirmed in vitro using primary bone cell cultures and
established cell lines. Elucidation of this mechanism provides for the
first time proof that inhibition of osteoblast apoptosis may represent
a novel therapeutic strategy for augmenting bone mass. Be that as it
may, several alternative mechanisms, including activation of lining
cells, have been proposed, and they may also contribute to the anabolic
effect of PTH (235 236 237 ). Nonetheless, lining cells cover at least 3
times more surface than osteoblasts. Therefore, conversion of lining
cells to bone-forming osteoblasts alone would be insufficient to cover
the increased cancellous bone area observed in rats and to account for
the expanded bone perimeter and the increased osteocyte number and
density observed with PTH treatment in mice (218 ).
Daily subcutaneous injections of PTH are safe and effective in the treatment of patients with corticosteroid-induced osteoporosis (230 ). The elucidation of the importance of osteoblast and osteocyte apoptosis in the mechanism of glucocorticoid-induced osteoporosis, and the elucidation of the importance of preventing apoptosis in the anabolic effects of PTH on bone, readily explain how PTH can be such an effective therapy in this condition. Hence, PTH and perhaps future PTH mimetics represent, for the first time, pathophysiology-based, i.e., rational as opposed to empirical, pharmacotherapies for osteopenias, in particular, those in which osteoblast progenitor formation is suppressed. In any case, future studies to assess the antifracture efficacy of these compounds will be needed before their effectiveness for the management of osteoporosis can be established.
B. Bisphosphonates and calcitonin
Bisphosphonates, stable analogs of pyrophosphate, and calcitonin
are potent inhibitors of bone resorption and effective therapies for
the management of osteoporosis and other diseases characterized by bone
loss (238 239 ). The main mechanism of the antiresorptive actions of
these agents is decreased development of osteoclast progenitors,
decreased osteoclast recruitment, and promotion of apoptosis of
mature osteoclasts leading to a slowing rate of bone remodeling (133 240 241 242 ). Nonetheless, the antifracture efficacy of these agents is
disproportional to their effect on bone mass (243 ), suggesting an
additional effect on bone strength unrelated to effects on bone
resorption. Moreover, long-term treatment of human and nonhuman
primates with bisphosphonates has been shown to increase wall
thickness, an index of increased osteoblast numbers or activity
(244 245 246 ), raising the possibility that they may not only inhibit bone
resorption, but may also have a positive effect on bone formation. An
explanation for this evidence is now provided by studies demonstrating
that bisphosphonates such as etidronate, alendronate, pamidronate,
olpadronate, or amino-olpadronate (IG9402, a bisphosphonate that lacks
antiresorptive activity), as well as calcitonin have antiapoptotic
effects on osteoblasts and osteocytes (219 ). These effects are
associated with a rapid increase in the phosphorylated fraction of
extracellular regulated signal kinases (ERKs) and are blocked by
specific inhibitors of ERK activation. In agreement with the in
vitro results, alendronate abolishes the increase in the
prevalence of vertebral, cancellous bone osteocyte and osteoblasts
apoptosis induced by administration of prednisolone in mice. These
findings raise for the first time the possibility that increased
survival of osteoblasts and osteocytes may both contribute to the
efficacy of bisphosphonates and calcitonin in the management of disease
states due to loss of bone.
If both "antiresorptive" and "anabolic" agents
[e.g., intermittent PTH] prevent osteoblast and osteocyte
apoptosis, why is increased formation so much more apparent in the case
of the "anabolic" agents? The discussion of physiological bone
regeneration in the beginning of this review article provides an
answer. Bone formation occurs only on sites of previous osteoclastic
bone resorption, i.e., on sites undergoing remodeling. Each
remodeling cycle is a transaction that, once consummated, is
irrevocable. Therefore, agents with antiapoptotic properties that do
not have antiresorptive/antiremodeling properties, i.e.,
they do not decrease the number of remodeling units, are expected to
rebuild more bone and therefore increase the overall bone mass, because
of the greater number of profitable transactions. Hence, by decreasing
the prevalence of osteoblast apoptosis, agents with pure antiapoptotic
properties, such as intermittent PTH, can expand the pool of mature
osteoblasts at sites of new bone formation and allow these cells more
time to make bone, to a much greater degree than the antiresorptive
agents that also slow remodeling. However, in the case of either class
of agents, upholding the osteocyte-canalicular network by preventing
osteocyte apoptosis, should contribute to antifracture efficacy, over
and above that resulting from their effects on bone mass (Fig. 5). Therefore, the distinction between
antiresorptive and anabolic agents may be more apparent than real when
it comes to antifracture efficacy.
|
As discussed in Section VIII in this review, estrogen and
androgen deficiency increase osteoblast and osteocyte apoptosis in
humans, rats, and mice; and these changes have been shown to be
reversed by replacement therapy, at least in mice (132 144 184 190 ).
In full agreement with these in vivo observations,
17ß-estradiol inhibits osteoblast and osteocyte apoptosis in
vitro. The antiapoptotic effect of 17ß-estradiol on osteoblasts
and osteocytes require the presence of the estrogen receptor- or
-ß (249 ). Nonetheless, unlike the classical mechanism of estrogen
receptor action that involves direct or indirect interaction with the
transcriptional apparatus, the estrogen receptor-dependent
antiapoptotic effect of 17ß-estradiol is due to rapid (within 5 min)
phosphorylation of ERKs (250 ). Moreover, the antiapoptotic effect of
17ß-estradiol can be reproduced by 17-estradiol, a compound
thought of as an inactive analog of 17ß-estradiol, as well as a
membrane-impermeable conjugate of 17ß-estradiol with BSA
(17ßE2-BSA). Numerous effects of estrogen have
been observed over the last few years in a variety of cell types,
including osteoblasts, the rapidity of which makes a genomic
mechanism of action unlikely (251 252 253 254 255 256 ). Many of these rapid actions
have been attributed to the ability of estrogen to act at the cell
membrane on a membrane-associated estrogen receptor (257 258 259 260 ). The
antiapoptotic effects of estrogen on osteoblasts and osteocytes fall
into this category of "nongenomic" actions. Based on this, the term
"activators of non-genomic estrogen-like signaling" (ANGELS), has
been coined for compounds that mimic the nongenomic effects of
estrogen, but have reduced classical estrogenic actions (261 ). A
paradigm of such agents is the synthetic compound estratriene-3-ol,
which has decreased transcriptional activity as compared with
17ß-estradiol (262 263 ), is a potent neuroprotective compound
(264 265 266 ), and does exhibit potent antiapoptotic effects on
osteoblasts and osteocytes in vitro. In support of the
hypothesis that ANGELS can be used as a novel, advantageous mode of
therapy for the augmentation of bone mass and/or fracture prevention in
diseases characterized by low bone mass and increased fragility,
preliminary evidence indicates that estratriene-3-ol increases BMD and
bone strength in both estrogen-replete and estrogen-deficient mice
(261 ). In view of this preclinical finding and the evidence that
androgen (190 ), as well as estrogen, have antiapoptotic effects on
osteoblasts and osteocytes, one is encouraged to think that estrogenic,
androgenic, or even nonsteroidal compounds that can activate
antiapoptotic, but not antiremodeling, signals on osteoblasts and
osteocytes, are candidates for future osteoporosis treatments that,
unlike existing ones that prevent or retard bone loss, may augment bone
mass.
|
XI. Summary and Conclusions |
|---|
|
Acknowledgments |
|---|
|
Footnotes |
|---|
1 Research from the author’s laboratory described in this review was
supported by the NIH (P01-AG13918, R01-AR43003), the Department of
Veterans Affairs (merit grant and a research enhancement award program,
REAP), and the 1999 Allied Signal Award for Research on Aging. 
|
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K. Horsch, H. de Wet, M. M. Schuurmans, F. Allie-Reid, A. C. B. Cato, J. Cunningham, J. M. Burrin, F. S. Hough, and P. A. Hulley Mitogen-Activated Protein Kinase Phosphatase 1/Dual Specificity Phosphatase 1 Mediates Glucocorticoid Inhibition of Osteoblast Proliferation Mol. Endocrinol., December 1, 2007; 21(12): 2929 - 2940. [Abstract] [Full Text] [PDF]
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S. C. Manolagas and M. Almeida Gone with the Wnts: {beta}-Catenin, T-Cell Factor, Forkhead Box O, and Oxidative Stress in Age-Dependent Diseases of Bone, Lipid, and Glucose Metabolism Mol. Endocrinol., November 1, 2007; 21(11): 2605 - 2614. [Abstract] [Full Text] [PDF]
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M. Almeida, L. Han, M. Martin-Millan, L. I. Plotkin, S. A. Stewart, P. K. Roberson, S. Kousteni, C. A. O'Brien, T. Bellido, A. M. Parfitt, et al. Skeletal Involution by Age-associated Oxidative Stress and Its Acceleration by Loss of Sex Steroids J. Biol. Chem., September 14, 2007; 282(37): 27285 - 27297. [Abstract] [Full Text] [PDF]
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M. Almeida, L. Han, M. Martin-Millan, C. A. O'Brien, and S. C. Manolagas Oxidative Stress Antagonizes Wnt Signaling in Osteoblast Precursors by Diverting beta-Catenin from T Cell Factor- to Forkhead Box O-mediated Transcription J. Biol. Chem., September 14, 2007; 282(37): 27298 - 27305. [Abstract] [Full Text] [PDF]
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S. M. Sharma, A. Bronisz, R. Hu, K. Patel, K. C. Mansky, S. Sif, and M. C. Ostrowski MITF and PU.1 Recruit p38 MAPK and NFATc1 to Target Genes during Osteoclast Differentiation J. Biol. Chem., May 25, 2007; 282(21): 15921 - 15929. [Abstract] [Full Text] [PDF]
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M. Ishijima, K. Tsuji, S. R Rittling, T. Yamashita, H. Kurosawa, D. T Denhardt, A. Nifuji, Y. Ezura, and M. Noda Osteopontin is required for mechanical stress-dependent signals to bone marrow cells J. Endocrinol., May 1, 2007; 193(2): 235 - 243. [Abstract] [Full Text] [PDF]
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P. Chavassieux, E. Seeman, and P. D. Delmas Insights into Material and Structural Basis of Bone Fragility from Diseases Associated with Fractures: How Determinants of the Biomechanical Properties of Bone Are Compromised by Disease Endocr. Rev., April 1, 2007; 28(2): 151 - 164. [Abstract] [Full Text] [PDF]
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D. S. Perrien, N. S. Akel, P. K. Edwards, A. A. Carver, M. S. Bendre, F. L. Swain, R. A. Skinner, W. R. Hogue, K. M. Nicks, T. M. Pierson, et al. Inhibin A Is an Endocrine Stimulator of Bone Mass and Strength Endocrinology, April 1, 2007; 148(4): 1654 - 1665. [Abstract] [Full Text] [PDF]
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F. Grassi, X. Fan, J. Rahnert, M. N. Weitzmann, R. Pacifici, M. S. Nanes, and J. Rubin Bone Re/Modeling Is More Dynamic in the Endothelial Nitric Oxide Synthase(-/-) Mouse Endocrinology, September 1, 2006; 147(9): 4392 - 4399. [Abstract] [Full Text] [PDF]
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S. J. Allison, P. Baldock, A. Sainsbury, R. Enriquez, N. J. Lee, E.-J. D. Lin, M. Klugman, M. During, J. A. Eisman, M. Li, et al. Conditional Deletion of Hypothalamic Y2 Receptors Reverts Gonadectomy-induced Bone Loss in Adult Mice J. Biol. Chem., August 18, 2006; 281(33): 23436 - 23444. [Abstract] [Full Text] [PDF]
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D. S. Perrien, S. J. Achenbach, S. E. Bledsoe, B. Walser, L. J. Suva, S. Khosla, and D. Gaddy Bone Turnover across the Menopause Transition: Correlations with Inhibins and Follicle-Stimulating Hormone J. Clin. Endocrinol. Metab., May 1, 2006; 91(5): 1848 - 1854. [Abstract] [Full Text] [PDF]
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M. Almeida, L. Han, C. A. O'Brien, S. Kousteni, and S. C. Manolagas Classical Genotropic Versus Kinase-Initiated Regulation of Gene Transcription by the Estrogen Receptor {alpha} Endocrinology, April 1, 2006; 147(4): 1986 - 1996. [Abstract] [Full Text] [PDF]
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S. C. Manolagas Choreography from the Tomb: An Emerging Role of Dying Osteocytes in the Purposeful, and Perhaps Not So Purposeful, Targeting of Bone Remodeling IBMS BoneKEy, January 1, 2006; 3(1): 5 - 14. [Full Text] [PDF]
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H. Ha, J.-H. Lee, H.-N. Kim, H.-M. Kim, H. B. Kwak, S. Lee, H.-H. Kim, and Z. H. Lee {alpha}-Lipoic Acid Inhibits Inflammatory Bone Resorption by Suppressing Prostaglandin E2 Synthesis J. Immunol., January 1, 2006; 176(1): 111 - 117. [Abstract] [Full Text] [PDF]
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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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N. Young, N. Mikhalkevich, Y. Yan, D. Chen, and W.-p. Zheng Differential Regulation of Osteoblast Activity by Th Cell Subsets Mediated by Parathyroid Hormone and IFN-{gamma} J. Immunol., December 15, 2005; 175(12): 8287 - 8295. [Abstract] [Full Text] [PDF]
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T. Bellido, A. A. Ali, I. Gubrij, L. I. Plotkin, Q. Fu, C. A. O'Brien, S. C. Manolagas, and R. L. Jilka Chronic Elevation of Parathyroid Hormone in Mice Reduces Expression of Sclerostin by Osteocytes: A Novel Mechanism for Hormonal Control of Osteoblastogenesis Endocrinology, November 1, 2005; 146(11): 4577 - 4583. [Abstract] [Full Text] [PDF]
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E. Gazzerro, V. Deregowski, S. Vaira, and E. Canalis Overexpression of Twisted Gastrulation Inhibits Bone Morphogenetic Protein Action and Prevents Osteoblast Cell Differentiation in Vitro Endocrinology, September 1, 2005; 146(9): 3875 - 3882. [Abstract] [Full Text] [PDF]
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X. Wu, E.-Y. Ahn, M. A. McKenna, H. Yeo, and J. M. McDonald Fas Binding to Calmodulin Regulates Apoptosis in Osteoclasts J. Biol. Chem., August 19, 2005; 280(33): 29964 - 29970. [Abstract] [Full Text] [PDF]
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L. E. Broker, F. A.E. Kruyt, and G. Giaccone Cell Death Independent of Caspases: A Review Clin. Cancer Res., May 1, 2005; 11(9): 3155 - 3162. [Abstract] [Full Text] [PDF]
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A. M. Vertino, C. M. Bula, J.-R. Chen, M. Almeida, L. Han, T. Bellido, S. Kousteni, A. W. Norman, and S. C. Manolagas Nongenotropic, Anti-Apoptotic Signaling of 1{alpha},25(OH)2-Vitamin D3 and Analogs through the Ligand Binding Domain of the Vitamin D Receptor in Osteoblasts and Osteocytes: MEDIATION BY Src, PHOSPHATIDYLINOSITOL 3-, AND JNK KINASES J. Biol. Chem., April 8, 2005; 280(14): 14130 - 14137. [Abstract] [Full Text] [PDF]
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A. Schneider, L. M. Kalikin, A. C. Mattos, E. T. Keller, M. J. Allen, K. J. Pienta, and L. K. McCauley Bone Turnover Mediates Preferential Localization of Prostate Cancer in the Skeleton Endocrinology, April 1, 2005; 146(4): 1727 - 1736. [Abstract] [Full Text] [PDF]
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K. Kaabeche, H. Guenou, D. Bouvard, N. Didelot, A. Listrat, and P. J. Marie Cbl-mediated ubiquitination of {alpha}5 integrin subunit mediates fibronectin-dependent osteoblast detachment and apoptosis induced by FGFR2 activation J. Cell Sci., March 15, 2005; 118(6): 1223 - 1232. [Abstract] [Full Text] [PDF]
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H. Zhao, F. P. Ross, and S. L. Teitelbaum Unoccupied {alpha}v{beta}3 Integrin Regulates Osteoclast Apoptosis by Transmitting a Positive Death Signal Mol. Endocrinol., March 1, 2005; 19(3): 771 - 780. [Abstract] [Full Text] [PDF]
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M. Ohishi, Y. Matsumura, D. Aki, R. Mashima, K. Taniguchi, T. Kobayashi, T. Kukita, Y. Iwamoto, and A. Yoshimura Suppressors of Cytokine Signaling-1 and -3 Regulate Osteoclastogenesis in the Presence of Inflammatory Cytokines J. Immunol., March 1, 2005; 174(5): 3024 - 3031. [Abstract] [Full Text] [PDF]
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J.-R. Chen, L. I. Plotkin, J. I. Aguirre, L. Han, R. L. Jilka, S. Kousteni, T. Bellido, and S. C. Manolagas Transient Versus Sustained Phosphorylation and Nuclear Accumulation of ERKs Underlie Anti-Versus Pro-apoptotic Effects of Estrogens J. Biol. Chem., February 11, 2005; 280(6): 4632 - 4638. [Abstract] [Full Text] [PDF]
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J. D. Veldhuis, J. N. Roemmich, E. J. Richmond, A. D. Rogol, J. C. Lovejoy, M. Sheffield-Moore, N. Mauras, and C. Y. Bowers Endocrine Control of Body Composition in Infancy, Childhood, and Puberty Endocr. Rev., February 1, 2005; 26(1): 114 - 146. [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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H. W. Goderie-Plomp, M. van der Klift, W. de Ronde, A. Hofman, F. H. de Jong, and H. A. P. Pols Endogenous Sex Hormones, Sex Hormone-Binding Globulin, and the Risk of Incident Vertebral Fractures in Elderly Men and Women: The Rotterdam Study J. Clin. Endocrinol. Metab., July 1, 2004; 89(7): 3261 - 3269. [Abstract] [Full Text] [PDF]
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F. Stossi, D. H. Barnett, J. Frasor, B. Komm, C. R. Lyttle, and B. S. Katzenellenbogen Transcriptional Profiling of Estrogen-Regulated Gene Expression via Estrogen Receptor (ER) {alpha} or ER{beta} in Human Osteosarcoma Cells: Distinct and Common Target Genes for These Receptors Endocrinology, July 1, 2004; 145(7): 3473 - 3486. [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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R. Gruber, B. Kandler, C. Jindra, G. Watzak, and G. Watzek Dental Pulp Fibroblasts Contain Target Cells for Lysophosphatidic Acid Journal of Dental Research, June 1, 2004; 83(6): 491 - 495. [Abstract] [Full Text] [PDF]
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P. V. N. Bodine, W. Zhao, Y. P. Kharode, F. J. Bex, A.-J. Lambert, M. B. Goad, T. Gaur, G. S. Stein, J. B. Lian, and B. S. Komm The Wnt Antagonist Secreted Frizzled-Related Protein-1 Is a Negative Regulator of Trabecular Bone Formation in Adult Mice Mol. Endocrinol., May 1, 2004; 18(5): 1222 - 1237. [Abstract] [Full Text] [PDF]
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M. Usui, Y. Yoshida, K. Tsuji, K. Oikawa, K. Miyazono, I. Ishikawa, T. Yamamoto, A. Nifuji, and M. Noda Tob deficiency superenhances osteoblastic activity after ovariectomy to block estrogen deficiency-induced osteoporosis PNAS, April 27, 2004; 101(17): 6653 - 6658. [Abstract] [Full Text] [PDF]
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R. S. Weinstein, D. Jia, C. C. Powers, S. A. Stewart, R. L. Jilka, A. M. Parfitt, and S. C. Manolagas The Skeletal Effects of Glucocorticoid Excess Override Those of Orchidectomy in Mice Endocrinology, April 1, 2004; 145(4): 1980 - 1987. [Abstract] [Full Text] [PDF]
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D. Karasik, M. T. Hannan, L. A. Cupples, D. T. Felson, and D. P. Kiel Genetic Contribution to Biological Aging: The Framingham Study J. Gerontol. A Biol. Sci. Med. Sci., March 1, 2004; 59(3): B218 - B226. [Abstract] [Full Text] [PDF]
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S. Evio, A. Tiitinen, K. Laitinen, O. Ylikorkala, and M. J. Valimaki Effects of Alendronate and Hormone Replacement Therapy, Alone and in Combination, on Bone Mass and Markers of Bone Turnover in Elderly Women with Osteoporosis J. Clin. Endocrinol. Metab., February 1, 2004; 89(2): 626 - 631. [Abstract] [Full Text] [PDF]
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E. Hay, J. Lemonnier, O. Fromigue, H. Guenou, and P. J. Marie Bone Morphogenetic Protein Receptor IB Signaling Mediates Apoptosis Independently of Differentiation in Osteoblastic Cells J. Biol. Chem., January 16, 2004; 279(3): 1650 - 1658. [Abstract] [Full Text] [PDF]
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F. E. Vegni, C. Corradini, G. Privitera, T. Sugiyama, H. Tanaka, S. Kawai, P. D. Miller, K. E. Fuller, D. M. Black, J. Bilezikian, et al. Effects of Parathyroid Hormone and Alendronate Alone or in Combination in Osteoporosis N. Engl. J. Med., January 8, 2004; 350(2): 189 - 192. [Full Text] [PDF]
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 G. Barera, S. Beccio, M. C. Proverbio, and S. Mora Longitudinal changes in bone metabolism and bone mineral content in children with celiac disease during consumption of a gluten-free diet Am. J. Clinical Nutrition, January 1, 2004; 79(1): 148 - 154. [Abstract] [Full Text] [PDF]
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X. Wu, M. A. McKenna, X. Feng, T. R. Nagy, and J. M. McDonald Osteoclast Apoptosis: The Role of Fas in Vivo and in Vitro Endocrinology, December 1, 2003; 144(12): 5545 - 5555. [Abstract] [Full Text] [PDF]
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J. N. VanHouten and J. J. Wysolmerski Low Estrogen and High Parathyroid Hormone-Related Peptide Levels Contribute to Accelerated Bone Resorption and Bone Loss in Lactating Mice Endocrinology, December 1, 2003; 144(12): 5521 - 5529. [Abstract] [Full Text] [PDF]
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S. Nakayamada, Y. Okada, K. Saito, M. Tamura, and Y. Tanaka {beta}1 Integrin/Focal Adhesion Kinase-mediated Signaling Induces Intercellular Adhesion Molecule 1 and Receptor Activator of Nuclear Factor {kappa}B Ligand on Osteoblasts and Osteoclast Maturation J. Biol. Chem., November 14, 2003; 278(46): 45368 - 45374. [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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G. Passeri, G. Pini, L. Troiano, R. Vescovini, P. Sansoni, M. Passeri, P. Gueresi, R. Delsignore, M. Pedrazzoni, and C. Franceschi Low Vitamin D Status, High Bone Turnover, and Bone Fractures in Centenarians J. Clin. Endocrinol. Metab., November 1, 2003; 88(11): 5109 - 5115. [Abstract] [Full Text] [PDF]
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G. Van den Berghe, D. Van Roosbroeck, P. Vanhove, P. J. Wouters, L. De Pourcq, and R. Bouillon Bone Turnover in Prolonged Critical Illness: Effect of Vitamin D J. Clin. Endocrinol. Metab., October 1, 2003; 88(10): 4623 - 4632. [Abstract] [Full Text] [PDF]
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 S. S. Budden and M. E. Gunness Possible Mechanisms of Osteopenia in Rett Syndrome: Bone Histomorphometric Studies J Child Neurol, October 1, 2003; 18(10): 698 - 702. [Abstract] [PDF]
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F. Elefteriou, S. Takeda, X. Liu, D. Armstrong, and G. Karsenty Monosodium Glutamate-Sensitive Hypothalamic Neurons Contribute to the Control of Bone Mass Endocrinology, September 1, 2003; 144(9): 3842 - 3847. [Abstract] [Full Text] [PDF]
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 S. Kim, T. Koga, M. Isobe, B. E. Kern, T. Yokochi, Y. E. Chin, G. Karsenty, T. Taniguchi, and H. Takayanagi Stat1 functions as a cytoplasmic attenuator of Runx2 in the transcriptional program of osteoblast differentiation Genes & Dev., August 15, 2003; 17(16): 1979 - 1991. [Abstract] [Full Text] [PDF]
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N. A. McHugh, H. M. Vercesi, R. W. Egan, and J. A. Hey Receptor activator of NF-{kappa}B ligand arrests bone growth and promotes cortical bone resorption in growing rats J Appl Physiol, August 1, 2003; 95(2): 672 - 676. [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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A. M. Delany, I. Kalajzic, A. D. Bradshaw, E. H. Sage, and E. Canalis Osteonectin-Null Mutation Compromises Osteoblast Formation, Maturation, and Survival Endocrinology, June 1, 2003; 144(6): 2588 - 2596. [Abstract] [Full Text] [PDF]
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S. S. Ahuja, S. Zhao, T. Bellido, L. I. Plotkin, F. Jimenez, and L. F. Bonewald CD40 Ligand Blocks Apoptosis Induced by Tumor Necrosis Factor {alpha}, Glucocorticoids, and Etoposide in Osteoblasts and the Osteocyte-Like Cell Line Murine Long Bone Osteocyte-Y4 Endocrinology, May 1, 2003; 144(5): 1761 - 1769. [Abstract] [Full Text] [PDF]
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Y. Hu, E. Chan, S. X. Wang, and B. Li Activation of p38 Mitogen-Activated Protein Kinase Is Required for Osteoblast Differentiation Endocrinology, May 1, 2003; 144(5): 2068 - 2074. [Abstract] [Full Text] [PDF]
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B. H. Ascott-Evans, N. Guanabens, S. Kivinen, B. G. A. Stuckey, C. H. Magaril, K. Vandormael, B. Stych, and M. E. Melton Alendronate Prevents Loss of Bone Density Associated With Discontinuation of Hormone Replacement Therapy: A Randomized Controlled Trial Arch Intern Med, April 14, 2003; 163(7): 789 - 794. [Abstract] [Full Text] [PDF]
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S. Cuzzocrea, E. Mazzon, L. Dugo, T. Genovese, R. Di Paola, Z. Ruggeri, E. Vegeto, A. P. Caputi, F. A. J. Van de Loo, D. Puzzolo, et al. Inducible Nitric Oxide Synthase Mediates Bone Loss in Ovariectomized Mice Endocrinology, March 1, 2003; 144(3): 1098 - 1107. [Abstract] [Full Text] [PDF]
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 S. Yakar and C. J. Rosen From Mouse to Man: Redefining the Role of Insulin-Like Growth Factor-I in the Acquisition of Bone Mass Experimental Biology and Medicine, March 1, 2003; 228(3): 245 - 252. [Abstract] [Full Text] [PDF]
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Y. Engelbrecht, H. de Wet, K. Horsch, C. R. Langeveldt, F. S. Hough, and P. A. Hulley Glucocorticoids Induce Rapid Up-Regulation of Mitogen-Activated Protein Kinase Phosphatase-1 and Dephosphorylation of Extracellular Signal-Regulated Kinase and Impair Proliferation in Human and Mouse Osteoblast Cell Lines Endocrinology, February 1, 2003; 144(2): 412 - 422. [Abstract] [Full Text] [PDF]
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S. L. Ferrari, L. Ahn-Luong, P. Garnero, S. E. Humphries, and S. L. Greenspan Two Promoter Polymorphisms Regulating Interleukin-6 Gene Expression Are Associated with Circulating Levels of C-Reactive Protein and Markers of Bone Resorption in Postmenopausal Women J. Clin. Endocrinol. Metab., January 1, 2003; 88(1): 255 - 259. [Abstract] [Full Text] [PDF]
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Y. Takeuchi, S. Watanabe, G. Ishii, S. Takeda, K. Nakayama, S. Fukumoto, Y. Kaneta, D. Inoue, T. Matsumoto, K. Harigaya, et al. Interleukin-11 as a Stimulatory Factor for Bone Formation Prevents Bone Loss with Advancing Age in Mice J. Biol. Chem., December 6, 2002; 277(50): 49011 - 49018. [Abstract] [Full Text] [PDF]
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A. Grey, Q. Chen, K. Callon, X. Xu, I. R. Reid, and J. Cornish The Phospholipids Sphingosine-1-Phosphate and Lysophosphatidic Acid Prevent Apoptosis in Osteoblastic Cells via a Signaling Pathway Involving Gi Proteins and Phosphatidylinositol-3 Kinase Endocrinology, December 1, 2002; 143(12): 4755 - 4763. [Abstract] [Full Text] [PDF]
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Abstract
I. Introduction
