The Tight Relationship Between Osteoclasts and the Immune System

1. Inflammation & Allergy - Drug Targets, 2012, 11, 181-187 181
2212-4055/12 $58.00+.00 © 2012 Bentham Science Publishers
The Tight Relationship Between Osteoclasts and the Immune System
Andrea Del Fattore1
and Anna Teti*,2
1
Regenerative Medicine Unit, Ospedale Pediatrico Bambino Gesù, Rome, Italy
2
Department of Experimental Medicine, University of L’Aquila, L’Aquila, Italy
Abstract: Osteoimmunology is an interdisciplinary field addressing the interplay between the skeletal and the immune
system. A substantial body of evidence demonstrated the existence of two-way regulatory mechanisms that affect both
systems, placing them in much closer association to each other than one could ever predict. Inflammatory diseases have
long been known to induce alterations in bone metabolism, and inflammatory cytokines play prominent roles in the
control of bone resorption, representing communication pathways bridging the two systems. Osteoclasts are particularly
linked to the immune cells because they belong to the monocyte/macrophage family, have tight relationships with B and T
cells, and differentiate in response to RANKL which is also produced by lymphocytes and regulates lymphopoiesis.
Osteoclasts are negatively regulated by cytokines and other factors known for their anti-inflammatory and immune
regulatory activity. Finally, they express immune co-receptor typical of immune cells which are indispensable for their
differentiation, thus leading to the hypothesis that osteoclasts are immune cells themselves. The underlying principle why
an immune cell is required to resorb bone has not yet been elucidated. Data from early literature suggest that the bone
matrix could trigger an innate immune response activating giant cells that could destroy large bone areas because of their
unique property of resorbing bone extracellularly. Bone resorption could though be prevented by the physical barrier
made by osteoblasts and lining cells, whose retraction would be required to give access to osteoclasts when specific
pathways signal their precursors to differentiate and mature osteoclasts to reach the uncovered bone surface.
Keywords: B cells, bone, immune system, osteoclast, osteoimmunology, RANKL, T cells.
INTRODUCTION
Bone is a multifaceted organ with numerous functions:
(i) mechanical, as support and site of muscle connection for
locomotion; (ii) protective, for essential organs, including
brain, visceral organs and bone marrow; (iii) metabolic, as a
reservoir of ions (especially calcium and phosphate) and for
the maintenance of their homeostasis, which is vital for the
body [1].
Bone is also an endocrine organ that regulates kidney
function through the FGF23 axis [2], and contributes to
energy consumption and insulin metabolism by complex
mechanisms involving leptin [3], serotonin [4] and
undercarboxylated osteocalcin [5, 6]. A recently discovered
function of this tissue is its ability to regulate male gonad
function and male fertility [7]. Last, but not least, bone is the
site where hematopoiesis and lymphopoiesis occur
physiologically [8].
The immune system is likewise intricate and supplies
individuals with defense from invading pathogens and
cancers. It detects a wide variety of agents, from viruses to
worms and tumor cells but, in order to function properly, it
must discriminate them from the body's own normal cells
and tissues. Physical barriers prevent pathogens from
penetrating the organism. If pathogens infringe these
barriers, the innate immune system provides an immediate,
non-specific response. If pathogens fruitfully elude the
innate response, then the adaptive immune system is
activated, representing a third layer of defense [9].
*Address correspondence to this author at the Department of Experimental
Medicine, Via Vetoio – Coppito 2, 67100 L’Aquila, Italy; Tel: +39 0862
433511; E-mail: annamaria.teti@univaq.it
Several overlaying and interconnected mechanisms have
evolved that regulate both systems. The interaction between
myeloid precursors of the monocyte/macrophage family and
osteoclasts was already recognized in the pioneering work in
which osteoclast defects in osteopetrosis could be rescued by
bone marrow transplantation and parabiosis [10, 11]. In early
studies, supernatant fluids from cultured human peripheral
blood leukocytes were found to induce osteoclast formation
[12, 13], and soluble factors secreted from antigen-
stimulated peripheral blood mononuclear cells came to be
known as Osteoclast-Activating Factors (OAFs). Following
these observations, InterLeukin-1 (IL-1) was later identified
as one of the pro-osteoclast cytokine in OAFs [14].
The interplay between bone and the immune system is
now well described. Many examples are available in the
literature. We know that (i) a subset of osteogenic cells,
called spindle-shaped N-cadherin-positive osteoblasts,
represents a critical component of the Hematopoietic Stem
Cell (HSC) niche and is essential for the maintenance of the
HSC pool that gives rise to all blood and immune cells [8];
(ii) the bone resorbing cells, osteoclasts, derive from the
monocyte/macrophage lineage and M-CSF (Macrophage-
Colony Stimulating Factor), a cytokine important for this
lineage, is even essential for osteoclast differentiation [15]. It
has also become apparent that, at least in vitro, cells
relatively far along into their differentiation toward antigen-
presenting dendritic cells hold the capability to
transdifferentiate into bone-resorbing osteoclasts [16, 17];
(iii) various soluble mediators of immune cell function,
including TNF- , IL-1 and IL-6, also regulate osteoblast and
osteoclast activity [18]. It is intriguing that alterations of
bone turnover and reduction of bone mass observed in
inflammatory diseases and in postmenopausal osteoporosis

2. 182 Inflammation & Allergy - Drug Targets, 2012, Vol. 11, No. 3 Del Fattore and Teti
could be in part due to the actions of immune cells and
cytokines [19].
This increasing body of evidence demonstrating the
intricate interactions between the immune system and bone
has led to the development of a new discipline, named
osteoimmunology [18, 20, 21]. This area of research is
particularly important for the comprehension of the
mechanisms underlying the profound alterations of bone
architecture caused by immune activation in inflammatory
diseases [22]. The word osteoimmunology is rather original.
It was coined in the late 1990s after milestone
demonstrations that T lymphocytes triggered bone loss by
stimulating osteoclast commitment and differentiation [23-
25]. This notion placed these two apparently different
systems in closer association than previously expected.
The field is just now expanding and we are currently
understanding the magnitude and relevance of these
interactions in human diseases. Exploring the boundary
between these two systems will contribute to a scientific
underpinning for novel therapeutic strategies to treat disease
conditions mediated by both systems. Here, we will provide
a brief description of the current knowledge on the
prominent role of the immune response in osteoclast biology
(Fig. 1) and will discuss the foundation for the need of this
interplay to bring about bone resorption.
Fig. (1). Concerted involvement of T cells and B cells in osteoclast
differentiation. The activation of B cells could occur through the
innate or adaptive immune response. Activated B cells express and
release osteoclastogenic molecules such as RANKL. Not depicted
here, B cells also produce OPG to counterbalance the effect of
RANKL (for interpretation of the references to color in this figure
legend, the reader is referred to the web version of this paper).
B CELLS AND OSTEOCLASTS
B cells represent a copious population of the bone
marrow and are known for their capacity to professionally
present antigens and to secrete antibodies upon
differentiation into plasma cells [26]. In the bone marrow, an
accurate spatial organization of B lymphopoiesis is observed.
The most primitive progenitors of B lymphocytes are in
intimate connection with the endosteal bone surface, and the
most mature are positioned in the central area of the bone
marrow [27]. This orderliness suggests that osteoblastic cells
in the endosteum, as well as stromal cells in the bone
marrow, produce factors important for the adjacent primitive
B lymphocyte precursors, such as Vascular Cell Adhesion
Molecule (VCAM)-like molecules, that regulate the homing
of lymphocyte precursors to bone marrow [27-29]. VCAM-1
expression can be stimulated by TNF- , IL-1 and IL-13
[30]. The interplay between bone and B cells is strengthened
by the evidence that cytokines involved in bone biology have
a direct effect on B lymphocyte differentiation.
Mice lacking RANK or RANKL, the receptor activator
of NF- B and its ligand responsible for osteoclast formation
(Fig. 1) [31], show severe osteopetrosis and are characterized
by a reduction of mature B220+
IgM+
/B220+
IgD+
B cells in
the spleen and lymph nodes [31]. Low number of B cells
observed in Rankl-/-
and Rank-/-
mice could be related to the
reduction of bone marrow cavities or to alterations of
stromal cells that influence B cell differentiation. For
example, Rankl-/-
mice show ectopic hematopoietic islands
containing proliferating precursor cells at the outer surfaces
of vertebral bodies [31], but further studies must be done to
analyze whether they are due to the reduced bone marrow
cavities or to a defect in the homing of precursors during the
switch from hepatic to bone marrow hematopoiesis. It is
interesting to note that both RANKL- and RANK-deficient
patients are also affected by osteopetrosis and, at least the
RANK-deficient subjects, present with hypogammaglobuli-
nemia associated with impairment in immunoglobulin-
secreting plasma cells [32, 33].
To study B cell differentiation, chimeric mice were made
by injecting fetal liver cells from wild type or Rankl-/-
mice
into sub-lethally irradiated Rag-/-
mice [34]. The bone
marrow of chimeric mice containing Rankl-/-
cells showed
normal levels of CD45R/B220+
CD25-
and CD45R/B220+
CD43+
pro-B cells, but displayed a reduction of CD45R/
B220+
CD43-
, CD45R/B220+
CD25+
and CD45R/B220+
sIgM+
B cells [34]. These results point to a prominent block in the
pro-B/pre-B cell maturation, suggesting that RANKL
controls early B cell differentiation.
Evidence in the molecular decoy receptor Osteoprote-
gerin (OPG) mutant mouse strain confirmed that the
RANKL/RANK/OPG interplay is important for the
maturation and function of B lymphocytes [35]. Ex vivo
experiments showed that Opg-/-
pro-B cells present with
increased proliferation in response to IL-7, and accumulation
of type 1 transitional B cells in spleen [35]. Moreover OPG
is a CD40 regulated gene in B cells and in dendritic cells,
and recent data demonstrated that B cells in vivo are most
likely the foremost producers of OPG in bone [36, 37].
Indeed, in the bone marrow of the osteoporotic B cell
knockout mice, the analysis of RANKL/OPG ratio displayed
a deficiency in OPG mRNA and protein expression.
Reconstitution of young B cell knockout mice with B cells
completely rescued the osteoporotic phenotype and
normalized OPG production [36, 37].
This important role of the B cell lineage in osteoclast
differentiation was also demonstrated in Pax5-deficient
mice. Pax5 is a member of a multigene family that encodes
the paired box (Pax) transcription factors and regulates pro-B
to pre-B transition. In the absence of Pax5, B cell
Preosteoclast
Multinucleated
osteoclast
Activated
osteoclast
Osteoblasts
B cells
Innate or
adaptive
Immune
response
Activated
B cell
RANKL
RANK
Activated
T cell
Bone
CFU-GM

3. The Tight Relationship Between Osteoclasts and the Immune System Inflammation & Allergy - Drug Targets, 2012, Vol. 11, No. 3 183
development in the bone marrow progresses up to an early
pro-B cell stage [34]. It has recently been shown that pro-B
cells from Pax5-deficient mice have the ability to take
several maturation pathways and could differentiate into
osteoclasts both in vitro and in vivo [34].
PU.1 is another transcription factor that plays an
important role in the development of both lymphoid and
myeloid lineages [38, 39]. Using retroviral infection, it was
shown that different concentrations of PU.1 regulate the
development of B cells and macrophages. Particularly, low
levels of PU.1 expression induce B cell development
whereas high levels stimulate macrophage differentiation
[40, 41]. It has also been reported that B220+
/IgM-
B
lymphocytes could differentiate into osteoclasts in vitro in
the presence of M-CSF and RANKL [42, 43], and at the
same time they express RANKL, supporting
osteoclastogenesis [42]. In an additional report, cocultures of
B220+
cells purified from bone marrow cells and stromal
ST2 cells in the presence of 1,25(OH)2 vitamin D3 gave rise
to resorbing osteoclasts [44].
Recently, it has also been proposed that myeloma cells,
which are tumoral plasma cells typically residing in the bone
marrow, could differentiate into osteoclasts. Osteolytic
lesions in advanced myeloma bone disease are not
characterized by high levels of osteoclasts. In contrast,
conglomerates of plasma cells with highly malignant
morphologic features usually occur in these sites, and could
form multinucleated cells [45, 46]. In vitro studies confirmed
that myeloma cells could generate polykarya with osteoclast-
like properties. They express the osteoclast-specific marker
TRAcP (Tartrate-Resistant Acid Phosphatase) and resorb
hydroxyapatite-containing bone-like substrates. Furthermore,
the discovery that in vivo polykarya have chromosome
translocations observed in myeloma cells strengthens the
concept that myeloma polykarya could differentiate into
resorbing osteoclasts and contribute to the bone devastation
observed in patients [47].
T CELLS AND OSTEOCLASTS
T cells are crucial mediators of the adaptive immune
response. They originate from HSCs that give rise to the
lymphoid lineage with initial commitment in the bone
marrow. The committed progenitors then migrate to the
thymus and differentiate into naïve T cells [48]. During
thymopoiesis, two major categories of mature T cells are
generated. They can be distinguished by the clonotypic
subunits contained within their T-cell receptor complexes:
/ T cells and / T cells. Most T cells are / T
lymphocytes that display either the CD4 or CD8 markers
[48]. Conversely, the majority of / cells lacks expression
of CD4 and CD8. Moreover, Natural Killer (NK) T cells are
another small subset of T cells, and express the / T-cell
receptor and the NK marker, NK1.1 [48, 49].
CD4+
positive lymphocytes can also be categorized in
Th1, Th2 and Th17 subpopulations, based on the type of
cytokine they express, IFN- /TNF- , IL-4 and IL-17,
respectively (Fig. 2) [50]. IFN- has a dual effect on
osteoclasts. In vitro experiments demonstrated that IFN-
strongly suppresses osteoclastogenesis [51], while in vivo
studies reported that IFN- promotes osteoclast formation
through stimulation of antigen-dependent T cell activation
[52]. TNF- stimulates osteoclastogenesis [53] while IL-4
inhibits it [50]. IL-17, also called IL-25, stimulates the
expression of many pro-inflammatory cytokines, including
IL-1, TNF- , IL-6, IL-8, and prostaglandin E2, and other
mediators important for inflammation and erosion of
cartilage and bone in rheumatoid arthritis. IL-17 is also a
potent inducer of RANKL expression in stromal cells and in
osteoblasts (Fig. 2), and has the power to induce joint
destruction in an IL-1-independent manner [54, 55]. It was
shown that blockade of IL-17 with an IL-17 receptor/human
IgG1 Fc fusion protein (muIL-17R:Fc) in adjuvant-induced
arthritis (AIA) in the rat, before the disease onset, attenuates
paw volume and reduces joint damage [56]. Furthermore, the
treatment after the onset of collagen-induced arthritis reduces
joint inflammation and cartilage and bone erosion [57].
Fig. (2). Osteoclast differentiation regulated by T cells. Th1 cells
produce TNF- that induces RANKL in stromal cells and also
stimulates osteoclast precursor cells to synergize with RANKL
signalling. Moreover they release IFN- that, at least in vitro,
suppresses osteoclastogenesis. Th2 cells have an inhibitory effect
on osteoclastogenesis releasing IL-4. Th17 cells stimulate
osteoclast differentiation/survival, producing RANKL and IL-17
that, in turn, induces RANKL expression in osteoblasts (for
interpretation of the references to color in this figure legend, the
reader is referred to the web version of this paper).
Th17 cells produce themselves the osteoclastogenic
cytokines RANKL (Fig. 2) and TNF- [58]. Nevertheless,
under basal conditions, T cells are not the main source of
RANKL since bone marrow from T cell deficient nude mice
does not show a reduction of RANKL mRNA levels [59].
Moreover, a subset of Th17 cells also produces small
amounts of IFN- [58-60].
T cells play an important role in bone loss induced by
estrogen deficiency. Several studies, mainly from the
Pacifici’s group, revealed that ovariectomy fails to induce
trabecular and cortical bone loss in nude mice [52, 61-64].
Same results were obtained whether wild type mice were
treated with Abatacept, an agent that induces T cells
Osteoblasts
CFU-GM
Preosteoclast
Multinucleated
osteoclast
Activated
osteoclast
Bone
RANKL
RANK
Th1 Th2 Th17
IFN-
RANKL
IFN-
IL-4
IL-4
IL-17
IL-17
TNFα
TNFα

4. 184 Inflammation & Allergy - Drug Targets, 2012, Vol. 11, No. 3 Del Fattore and Teti
apoptosis, or with the anti-inflammatory agent aspirin [65,
66]. These experiments suggest that T cells are key players
of estrogen deficiency-induced bone loss, as also
demonstrated by the fact that ovariectomy increases the
production of TNF- by T cells [67].
Recent evidence also suggests that T lymphocytes play
an unexpected critical role in the mechanisms of action of
ParaThyroid Hormone (PTH) in bone [61]. T cells express
the functional G protein coupled PTH receptor, PTH-1R
[68]. Chronic elevated production of PTH underlies a
pathological condition called hyperparathyroidism, which is
a cause of skeletal and extra-skeletal diseases. Primary
hyperparathyroidism is associated with increased bone
turnover and osteopenia [69-73], and secondary
hyperparathyroidism has been implicated in the pathogenesis
of senile osteoporosis [74].
Continuous PTH infusion mimics primary and secondary
hyperparathyroidism, while intermittent administration is an
approved anabolic treatment for osteoporosis [75]. T cells,
may contribute to the catabolic activity of PTH in vivo [61,
68]. Many data suggest that T lymphocytes could function as
permissive cells, stimulating stromal cells and osteoblasts to
support PTH-induced osteoclastogenesis [68]. However, it
has also been shown that continuous PTH treatment at doses
that mimic hyperparathyroidism fails to induce osteoclast
formation, bone resorption and cortical bone loss in T cell
deficient mice [68].
In the bone marrow there are activated memory T cells
that express ligands for molecules expressed by cells
belonging to the osteoblast lineage [76]. Particularly,
CD40L, through its binding to CD40, stimulates survival and
proliferation of stromal cells and osteoblasts [77]. Moreover
CD40L/CD40 signaling increases RANKL/OPG ratio in
stromal cells [68]. These alterations provide a molecular
justification for the reduced ability of stromal cells from T
cell deficient bone marrow to support osteoclastogenesis in
vitro [68]. Furthermore, through CD40L, T cells sensitize
stromal cells to PTH. Lastly, PTH increases CD40
expression in stromal cells derived from T cell repleted mice
but not from T cell deficient mice [68].
Interestingly, T cells also may play a role in the anabolic
response to intermittent PTH [78, 79]. Intermittent PTH
stimulates Wnt10b expression by bone marrow CD8+
T cells
and induces these cells to activate the canonical Wnt
signaling in pre-osteoblasts. Moreover, pre-osteoblasts of T
cell null mice show reduced Wnt signaling in responses to
intermittent PTH, which result in decreased trabecular bone
anabolism [79]. Therefore, T cells are likely to contribute to
both the catabolic and the anabolic role of PTH, suggesting
that T cell-osteoblast crosstalk pathways are central to the
balanced response to this hormone [61].
OSTEOCLAST – AN IMMUNE CELL?
Although the RANKL/RANK pathway has long been
considered indispensable for triggering osteoclast formation,
it is now recognized that it is insufficient and that parallel
signals are required for osteoclastogenesis to occur
physiologically. Various studies have shown that calcium
oscillations are mandatory for induction of osteoclast
formation, but the RANK intracellular signals are not
capable of inducing calcium mobilization [80]. Therefore,
additional signals must be triggered in osteoclast precursors
and these have been found to be associated with the
expression of immunoglobulin (Ig)-like receptors, which
typically regulate the activity of immune cells [81]. In
osteoclasts, these receptors, called OSteoClast-Associated
Receptor (OSCAR), Paired Ig-like Receptor-A (PIR-A),
Triggering Receptor Expressed on Myeloid cells-2 (TREM)
and Src homology 2 (SH2) domain-containing Inositol
Phosphatase-1 (SIRPbeta1), are associated with
Immunoreceptor Tyrosine-based Activation Motif (ITAM)-
harboring adaptor molecules DNAX-activating protein of 12
kD (DAP12) and Fc-Receptor common -subunit (FcR ).
The role of the DAP12 and FcR in osteoclast regulation has
been clarified using mice deficient in both DAP12 and FcR ,
which have a severe osteopetropic phenotype and lack
osteoclast formation [82]. Phosphorylation of the ITAM
sequence in DAP12 or FcR occurs after RANK activation,
allows the recruitment of Splenocyte Tyrosine Kinase (SYK)
through which the PhosphoLypase C (PLC ) is activated
and, in turn, triggers calcium oscillations. Calcium
mobilization activates the CAlcium/calModulin-dependent
protein Kinase type IV (CAMKIV), which contributes to c-
Fos and calcineurin activation, both cooperating to potentiate
the Nuclear Factor of Activated T cells c1 (NFATc1) auto-
amplification loop indispensable for induction of osteoclast-
specific genes [80]. Although the ligands for these receptors
are still unknown, it is believed that OSCAR and PIR-A are
activated by osteoblast-osteoclast precursor communication
signals, while TREM and SIRPbeta1 are triggered by cell
surface molecules expressed by the osteoclast precursor
itself [83].
Other molecules are now recognized to play dual roles in
the regulation of immune cells and osteoclasts. For instance,
a recent work [84] has shown that the transcription factor B
lymphocyte-induced maturation protein-1 (Blimp1), a
transcriptional repressor involved in the differentiation of B
lymphocytes toward plasma cells by direct repression of the
transcription factors Pax5, Bcl6 and Myc [85] stimulates
osteoclastogenesis by repressing the transcription factors
IFN Regulatory Factor-8 (IRF-8) and v-Maf musculo-
aponeurotic fibrosarcoma oncogene family, protein B
(MafB) both negatively affecting osteoclastogenesis [86, 87].
Recent studies suggest that osteoclasts could serve as
Antigen Presenting Cells (APC) to activate both CD4+
and
CD8+
cells [88]. Osteoclasts express Major Histocompatib-
ility Complex (MHC) classes I and II, CD86, CD80 and
CD40, and uptake soluble antigens. Moreover, they are able
to present allogenic antigens, activating T cells [88].
Based on the aforementioned evidence, it has been
proposed that osteoclasts are cells themselves belonging to
the immune system [89-91]. Their involvement in the
immune response and their origin from circulating
monocytes have indeed been recognized since many years
[92], although their relationship with macrophages has been
controversial [93]. However, their roles as immune cells or
immune response modulators have recently become clear
[94], and the ability of osteoclast precursors to enter the
bloodstream and circulate make them even more closely
related to other hematopoietic cells.

5. The Tight Relationship Between Osteoclasts and the Immune System Inflammation & Allergy - Drug Targets, 2012, Vol. 11, No. 3 185
It is interesting to note that osteoclasts are very efficient
and may destroy large amounts of bone in relatively short
time. Like immune cells, they are physiologically subjected
to various negative regulators, including OPG, IL-4, IFN-
and IFN- , that may antagonize their resorbing function [95],
preventing their differentiation or reducing their life span.
This further supports their role as integral immune cells
subjected to efficient repression.
It is however unclear why bone resorption must be
carried out by cells of the immune system [90, 91]. In 1985,
Chambers [96] proposed that the bone matrix can act in the
organism as something similar to a foreign body. Indeed, in
physiological conditions, the bone surface is separated by the
interstitial fluids by cells, either active osteoblasts or lining
cells (Fig. 3). This cell layer could represent a physical
barrier which segregates the bone from the immune system.
Only when the cell layer is removed, for example through
osteoblast or lining cell retraction or apoptosis [90, 91], the
bone matrix could be exposed and stimulate an innate
immune response. Still the question remains why do we need
an osteoclast and not a regular foreign body giant cell to
destroy the bone matrix. Our view is that an osteoclast is
needed because the bone surface is so large and an
extracellular mechanism of bone resorption is required for its
disruption rather than a regular phagocytic process [91].
Fig. (3). Uncovered bone matrix recognized as a foreign body.
Bone is always covered by cells, osteoblasts or lining cells (1).
Microenvironmental changes may bring about osteoblast retraction,
reduced activity or apoptosis (2). The resulting uncovered bone
matrix could be recognized as a foreign body and activate immune
cells which induce osteoclast formation and bone resorption (3) (for
interpretation of the references to color in this figure legend, the
reader is referred to the web version of this paper).
CONCLUSIONS
Osteoclasts have been recognized for many years as the
bone resorbing cells, but recent reports indicate that they
have multiple additional functions, which affect the activity
of cells in and around the bone.
It is now well established that bone is a tissue of central
importance which interacts very tightly not only with cells of
the immune system, but also with other organs and tissues.
Despite extensive cross-regulation between bone and the
immune system, however, the mechanisms by which these
systems regulate each other are still poorly understood.
However, the field is progressively advancing and we expect
that this multidisciplinary area will rapidly provide new
clues explaining the meaning of the immune regulation of
bone resorption in health and diseases.
ACKNOWLEDGEMENTS
We thank Dr. Rita Di Massimo for excellent assistance in
editing this manuscript. The original work was supported by
the Telethon grants N. GGP06019 and GGP09018, and by
grants from the Ministry of Health “Rare Diseases”, from E-
rare (project OSTEOPETR), from the Swiss Bridge and from
the Italian Association for Cancer Research (AIRC) to AT.
ADF is supported by the 2010 International Bone and
Mineral Society Gideon and Sevgi Rodan Fellowship.
CONFLICT OF INTEREST
Authors declare that no conflict of interest exists.
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Received: August 12, 2010 Revised: June 30, 2011 Accepted: July 7, 2011