REVIEWS

Osteoimmunology: shared
mechanisms and crosstalk between
the immune and bone systems
Hiroshi Takayanagi
Abstract | Osteoimmunology is an interdisciplinary research field focused on the molecular
understanding of the interplay between the immune and skeletal systems. Although
osteoimmunology started with the study of the immune regulation of osteoclasts, its scope
has been extended to encompass a wide range of molecular and cellular interactions,
including those between osteoblasts and osteoclasts, lymphocytes and osteoclasts, and
osteoblasts and haematopoietic cells. Therefore, the two systems should be understood to
be integrated and operating in the context of the ‘osteoimmune’ system, a heuristic concept
that provides not only a framework for obtaining new insights by basic research, but also a
scientific basis for the discovery of novel treatments for diseases related to both systems.

Osteoclastogenesis
A process whereby
haematopoietic stem cells
differentiate into
multinucleated osteoclasts
with bone-resorbing activity.
Department of Cell Signaling,
Graduate School, Tokyo
Medical and Dental
University, Yushima 1-5-45,
Bunkyo-ku, Tokyo 113-8549;
COE Program for Frontier
Research on Molecular
Destruction and
Reconstruction of Tooth and
Bone, Tokyo Medical and
Dental University; and
SORST, Japan Science and
Technology Agency, Honcho
4-1-8, Kawaguchi, Saitama
332-0012, Japan.
e-mail: taka.csi@tmd.ac.jp
doi:10.1038/nri2062
The close relationship between the immune and
skeletal systems has long been appreciated, since the
pioneering works in the early 1970s (REFS 1–4). Soluble
factors secreted from antigen-stimulated immune
cells were known as osteoclast-activating factors 1,
one of which was revealed to be interleukin-1 (IL-1)3.
Since then, accumulating evidence has indicated that
the immune and skeletal systems share a number of
regulatory molecules including cytokines, recep-
tors, signalling molecules and transcription factors5,6.
Furthermore, immune cells are formed and haema-
topoietic stem cells (HSCs) are maintained in the bone
marrow where they interact with bone cells. Therefore,
the evidence that the physiology and pathology of one
system might affect the other is compelling (FIG. 1) and
the term osteoimmunology was coined to cover these
overlapping scientific fields7.
The most typical example of the interaction between
the skeletal and immune systems is seen in the abnor-
mal and/or prolonged activation of the immune system
in autoimmune diseases, such as rheumatoid arthritis,
that lead to bone destruction caused by bone-resorbing
osteoclasts8,9. Osteoclast differentiation is regulated
by macrophage colony-stimulating factor (M-CSF)10
and receptor activator of nuclear factor-κB (NF-κB)
ligand (RANKL; also known as TNFSF11), a tumour-
necrosis factor (TNF)-family cytokine11,12. A mutation
in the M-CSF gene causes a defect in both macrophage
and osteoclast formation, pointing to the notion that
immune cells and bone cells are derived from the same
origin13. RANKL is not only expressed by the bone-
forming osteoblasts that support osteoclastogenesis in
bone tissue, but also by activated T cells, indicating
that osteoclastic bone resorption is influenced by the
immune system12,14. As the analyses of osteoclasts and
RANKL have been at the forefront of recent progress in
osteoimmunology, this Review first focuses on the sig-
nalling mechanism of RANKL and the role of immune
mediators in osteoclastic signal transduction.
However, M-CSF and RANKL are not the only fac-
tors linking the immune and skeletal systems. Targeted
disruption of various immunomodulatory molecules
has resulted in unexpected phenotypes in the skel-
etal system (TABLE 1; Supplementary information S1
(table)). It is worth noting that extracellular matrix
components, such as osteopontin, also have crucial
roles in both systems. Moreover, recent studies have
indicated that osteoblasts and even osteoclasts are
involved in the maintenance and regulation of HSCs,
indicating the crucial role of skeletal cells in both the
haematopoietic and immune systems15–18. Clinically, the
effectiveness of TNF-specific antibody therapy against
bone destruction in patients with rheumatoid arthri-
tis also highlights the importance of the relationship
between the immune and skeletal systems19. Therefore,
osteoimmunology is becoming increasingly important
for understanding the pathogenesis of, and developing
new therapeutic strategies for, diseases affecting both

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© 2007 Nature Publishing Group

Osteoporosis
A metabolic or ageing-related
(often occurring in post-
menopausal women) disease in
which low bone mineral density
causes bone fragility.
Mechanotransduction
A process by which the
mechanical stress (such as
gravity, loading and tension)
is converted to biological
responses, which in this case
control bone remodelling.
Osteopetrosis
A rare congenital disease
with extremely high bone mass
and low strength (typically,
no bone-marrow formation
and no tooth eruption),
which results from impaired
differentiation or function of
osteoclasts.
NATURE REVIEWS | IMMUNOLOGY
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systems. Here I introduce the key cells and molecules Inputs
involved in the interactions between the bone and • Calcium intake
immune systems and summarize recent progress in • Mechanostress
• Ageing
this field. • Stress
• Tumour
Overview of the cells in the skeletal system • Infection
• Inflammation
The bony skeleton, the essential component of the
skeletal system, enables locomotive activity, the storage
of calcium and the harbouring of HSCs from which
immune cells are derived. This multifunctional organ
is characterized by calcified hard tissue composed of Controllers
• Immune system
type I collagen and highly organized deposits of calcium • Other regulatory
phosphate (hydroxyapatite)20. Although it seems to be systems
metabolically inert, bone is restructured at such a high
speed that approximately 10% of the total bone content is
replaced per year in adult vertebrates. This process, called
bone remodelling, is dependent on the dynamic balance
of bone formation and resorption, which are mediated Bone
by osteoblasts and osteoclasts, respectively. A delicate Bone marrow
regulation of this process is a prerequisite for normal
Haematopoietic cells
bone homeostasis (TABLE 1; Supplementary information
S1 (table)), and an imbalance is often linked to meta-
bolic bone diseases in humans, such as osteoporosis and
inflammatory bone loss21. Osteoblast Osteoclast
Osteoblasts are cells of mesenchymal origin that
secrete bone-matrix proteins and promote mineral-
ization20,21. The proliferation and differentiation of Osteocyte
osteoblasts are under the control of a number of solu-
ble factors and transcription factors such as RUNX2
(runt-related transcription factor 2) and OSTERIX
(also known as SP7) 22,23. Differentiated osteoblasts
Outputs
embedded in the bone matrix are called osteocytes, • Calcium metabolism
and might have a specific but as-yet unclear role in • Bone mass/quality
mechanotransduction20. (locomotion and
body support)
Osteoclasts are cells of haematopoietic origin that • Haematopoiesis
decalcify and degrade the bone matrix by acid decal-
cification and proteolytic degradation, respectively24. Figure 1 | The osteoimmune system. The skeletal
They are large, multinucleated cells formed by the system is involved in the regulation of three main
fusion of precursor cells of the monocyte–macrophage outputs that are related to calcium reserves,
locomotion and haematopoiesis. To maintain
lineage. In vitro osteoclast differentiation is supported
homeostasis while responding to various inputs
by mesenchymal cells (bone-marrow stromal cells or (such as nutrition, mechanical stress, ageing, and
osteoblasts) through cell–cell contact25, although there inflammation), the cells in the bone marrow are
has been little in vivo information about osteoclasto- controlled by the immune systems in concert with
genesis-supporting cells. Osteoclastogenic signals are other regulatory systems, such as the endocrine and
mediated by RANKL and its co-stimulatory signals, neural systems. As depicted, the bone system and the
in addition to M-CSF 5,11,12. The congenital lack of immune system in the bone-marrow microenvironment
osteoclasts leads to osteopetrosis, which is character- are regulated as if they were integrated in the context
ized by a high bone mass and a defect in bone-marrow of the osteoimmune system.
formation. Naturally occurring mutant mice or geneti-
cally modified mice with osteopetrosis have provided
insights into the molecular mechanism of osteoclast M-CSF
differentiation and function26 (TABLE 1; Supplementary M-CSF was first identified as an essential factor for
information S1 (table)): M-CSF and the transcription osteoclastogenesis. M-CSF transmits its signal to the cell
factor PU.1 are crucial for the proliferation and survival through the specific receptor cFMS, which is a member
of osteoclast precursor cells; transcription factors such of the receptor tyrosine kinase superfamily. M-CSF is cru-
as cFOS, microphthalmia-associated transcription fac- cial for the proliferation and survival of precursor cells
tor (MITF) and NF-κB have been shown to be essential of osteoclasts as well as macrophages, mainly by activat-
for osteoclast differentiation; and factors such as cSRC, ing ERK (extracellular-signal-regulated kinase) through
VAV3, β3-integrin, chloride-channel family member GRB2 (growth-factor-receptor-bound protein 2) and
ClC7, vacuolar ATPase and cathepsin K are crucial for AKT through PI3K (phosphoinositide 3-kinase) 10.
osteoclast function26. M-CSF also stimulates the expression of RANK in
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Familial expansile osteolysis
(FEO). A rare autosomal-
dominant disorder resembling
Paget’s disease of bone (PDB),
characterized by the erosion of
long bones by progressive
osteoclastic resorption (the
constitutive active mutation
of RANK has been reported).
Paget’s disease of the bone
(PDB). A metabolic bone
disorder in which focal
abnormalities of increased
bone turnover (excessive
osteoclastic bone resorption
and irregular bone formation)
lead to bone pain and
deformity.
monocyte–macrophage precursor cells, thereby rendering
them able to efficiently respond to RANKL. PU.1, a mem-
ber of the ETS family of transcription factors, regulates the
development of macrophages and osteoclasts by control-
ling the expression of cFMS27. MITF, activated by M-CSF,
induces BCL-2 (B-cell lymphoma 2), which has a pivotal
role in cell survival28. The transgenic expression of BCL-2
rescues the osteopetrosis found in op/op mice (which are
deficient in M-CSF), indicating the main role of M-CSF as
a survival factor of osteoclast precursor cells29.
RANKL
The crucial role of RANKL in bone. It was unex-
pected both for bone biologists and for immunolo-
gists that the long-sought osteoclast-differentiation
factor expressed by osteoblasts would be the same
molecule expressed by T cells to stimulate dendritic
cells (DCs)30–33. This osteoclast-differentiation factor is
now called RANKL, or TNF-related activation-induced
cytokine (TRANCE), according to the nomenclature
of the immune system. RANKL, a type II membrane
protein, belongs to the TNF superfamily and contains a
C-terminal receptor-binding domain and a transmem-
brane domain. Its receptor, RANK, is a type I membrane
protein sharing high homology with CD40, and the
binding of RANKL to RANK is inhibited by the decoy
receptor osteoprotegerin (OPG)34,35. In bone, RANKL is
expressed by osteoclastogenesis-supporting cells, includ-
ing osteoblasts, in response to osteoclastogenic factors,
such as 1,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ),
prostaglandin E2 (PGE2) and parathyroid hormone, and
is a crucial determinant of the level of bone resorption
in vivo25. A series of genetically modified mice has clearly
shown that RANKL and its receptor RANK are indispen-
sable for osteoclastogenesis12,36, and human mutations
in RANK and OPG cause familial expansile osteolysis and

Table 1 | Bone phenotypes in mice deficient in osteoimmunoregulatory molecules

Disrupted osteoimmunomodulatory Osteoclast-mediated bone resorption Osteoblast-mediated Bone volume References
molecule bone formation
Differentiation Function
Cytokine or secreted protein
RANKL ↓ ND ND ↑ 12
Receptors, channels and membrane factors
DAP12/FcRγ ↓ ↓ ↓ ↑ 99
DC-STAMP ↓ ↓ ND ↑ 94
Plexin-A1 ↓ ↓ ↔ ↑ 97
IFNα/βR1 ↑ ND ↔ ↓ 72
IFNγR1 ↑* ND ND ND 73
EPHB4‡ ↓ ↓ ↑ ↑ 96
Adaptor and signalling molecules
TRAF6 ↓ ND ND ↑ 49
GAB2 ↓ ND ↔ ↑ 56
STAT1 ↑ ND ↑ ↑ 88
SOCS1/3 ↓* ND ND ND 90
Kinases and phosphatases
NIK ↓* ND ND ↔ 76
IKKβ ↓ ND ↓ ↑ 75
v
SHP1 (me /me ) v §
↑ ND ↓ ↓ 102
SHIP1 ↑ ↑ ND ↓ 104
Transcription factors
NF-κB p50/p52 ↓ ND ↔ ↑ 53
NFATc1 ↓ ND ↓ ↑ 63
NFATc2 ↔ ↔ ↓ ↓ 81
SHN3 ↔ ↔ ↑ ↑ 91
*Analysed in models of inflammatory bone loss. ‡Data in transgenic mice. §Naturally occurring mutant in brackets. See the full list of mutant mice in Supplementary
information S1 (table). ↑, increased; ↓, decreased; ↔, unchanged; DC-STAMP, dendritic-cell-specific transmembrane protein; EPHB4, ephrin receptor B4;
FcRγ, Fc receptor common γ-subunit; GAB2, growth-factor-receptor-bound-protein-2-associated binding protein 2; IFN, interferon; IKK-β, inhibitor of nuclear
factor-κB (IκB) kinase-β; ND, not determined; NFAT, nuclear factor of activated T cells; NIK, NF-κB-inducing kinase; RANKL, receptor activator of NF-κB ligand;
SHN3, Schnurri-3; SHIP1, SH2-domain-containing inositol-5-phosphatase; SHP1, SH2-domain-containing protein tyrosine phosphatase 1; SOCS, suppressor of
cytokine signalling; STAT1, signal transducer and activator of transcription 1; TRAF6, tumour-necrosis factor-receptor-associated factor 6.

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a Generation of osteoclast precursor b Early response to RANKL c Initial induction of NFATc1

cells by M-CSF

Unknown
ligand
M-CSF RANKL
Ig-like
cFMS RANK receptor

DAP12 Phosphorylation P
or FcRγ TRAF6 of ITAM P SYK PLCγ Ca2+
• Proliferation NFATc2
• Survival NFATc2 NFATc2
Co-stimulatory
signals NF-κB
Cytosol

Nucleus NFATc1

d Autoamplification of NFATc1 e Induction of osteoclast-specific genes

P P
SYK PLCγ Ca2+ SYK PLCγ Ca2+

cFOS CREB CaMKIV

Calcineurin
Calcineurin
AP1
Auto-amplification

MITF PU.1 Induction of

AP1 osteoclast-
NFATc1 NFATc1 CREB NFATc1 specific genes

Figure 2 | Spatiotemporal control of signal transduction during osteoclastogenesis. Osteoclast differentiation

is induced by M-CSF (macrophage colony-stimulating factor), RANKL (receptor activator of nuclear factor-κB
(NF-κB) ligand) and its co-stimulatory factor, immunoglobulin (Ig)-like receptor. a | Precursor-cell stage.
The binding of M-CSF to its receptor, cFMS, activates the proliferation and survival of osteoclast precursor cells
of the monocyte–macrophage lineage that express RANK. The co-stimulatory receptors might be stimulated from
early stages, although ligands of co-stimulatory receptors have yet to be identified. b | Proximal RANK signals.
RANKL binding to RANK results in the recruitment of TRAF6 (tumour-necrosis-factor-receptor-associated factor
6). At the same time, RANK activation results in the phosphorylation of the ITAM (immunoreceptor tyrosine-based
activation motif) in DAP12 and FcRγ (Fc-receptor common γ-subunit), both of which are adaptor proteins
associating with distinct Ig-like receptors. Ig-like receptor signals are called co-stimulatory signals for RANK.
c | Initial induction of NFATc1 (nuclear factor of activated T cells, cytoplasmic 1). NFATc1, a key transcription factor
for osteoclastogenesis, is initially induced by TRAF6-activated NF-κB and NFATc2 that is present in the cell before
RANKL stimulation. Phosphorylation of the ITAM in DAP12 (or FcRγ) results in the recruitment of spleen tyrosine
kinases (SYKs) that activate calcium signalling through phospholipase Cγ (PLCγ). d | Auto-amplification of NFATc1.
Calcium-signal-mediated persistent activation of NFATc1, as well as cooperation with activator protein 1 (AP1), is
a prerequisite for the robust induction of NFATc1. AP1 activation is mediated by the induction and activation of
cFOS by CaMKIV (calcium/calmodulin-dependent protein kinase type IV)-stimulated CREB (cyclic AMP
responsive-element-binding protein) and cFMS. The NFATc1 promoter is epigenetically activated through histone
acetylation and NFATc1 binds to an NFAT-binding site of its own promoter. e | In the nucleus, NFATc1 works
together with other transcription factors, such as AP1, PU.1, MITF (microphthalmia-associated transcription
factor) and CREB, to induce various osteoclast-specific genes, including TRAP (tartrate-resistant acid
phosphatase), cathepsin K and calcitonin receptor.

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juvenile Paget’s disease of the bone, respectively37. T cells
not only express RANKL on their membrane, but also
release it as a soluble form, although the in vivo function
of the soluble form remains to be clarified12,38.
Immunological functions of RANKL. Interestingly,
RANKL–/– mice have a defect in the development of
secondary lymphoid organs36 (a lack of lymph nodes
and abnormality in the spleen) and mammary glands39.
RANKL might regulate lymphotoxin expression in
lymph nodes, but the intact formation of Peyer’s
patches in RANKL–/– mice indicates a more complicated
mechanism that needs to be clarified12.
T cells that express RANKL have a positive role in DC
activation and survival in vitro30,40,41, indicating that the
RANKL–RANK system regulates DC function through
the T cell–DC interaction. However, DC development
and function are normal in RANKL–/– mice12 and the
function of RANKL in the eradication of pathogens
such as viruses has not been clearly observed in vivo42.
The inhibition of RANKL greatly decreases antiviral
responses in mice lacking CD40L, possibly because the
CD40L–CD40 system has a redundant role 42. On
the basis of this functional redundancy, the crucial role
of RANKL in the immune system might not be obvious
under physiological conditions.
RANKL was shown to have a pathological role in a
model of inflammatory bowel disease, indicating that
RANKL stimulates DC activation in vivo and acceler-
ates immune reactions under certain autoimmune con-
ditions43. On the other hand, RANKL is involved in the
generation of regulatory T cells in a diabetic model44.
In addition, RANKL expressed by keratinocytes in
the skin has a crucial role in the control of regulatory
T cells by modulating the function of Langerhans cells
and it suppresses autoimmune reactions induced by
CD40L45. These reports clearly indicate that RANKL
has an immunosuppressive role in vivo. In addition, a
recent report indicated that RANKL is a chemotactic
factor for RANK-expressing tumour cells as well as
osteoclasts, indicating that RANKL also functions
as a chemokine46. Therefore, although the function of
RANKL in the immune system needs to be elucidated
in more detail, it is clear that RANKL is one of the
most important molecules that explicitly link the bone
and immune systems.
Cellular response to RANKL. The intracellular signal-
ling pathways of RANKL have been extensively studied
in the context of osteoclast differentiation11 (FIG. 2).
RANK lacks intrinsic enzymatic activity in its intra-
cellular domain, and transduces signalling by recruiting
adaptor molecules such as the TNF-receptor-associated
factor (TRAF) family of proteins47. Among the TRAF
proteins, gene-disruption studies48,49 followed by inten-
sive molecular analyses identified TRAF6 as the main
adaptor molecule that links RANK to the differentiation
and function of osteoclasts50–52. By an as-yet-unknown
mechanism, RANKL binding to RANK induces the
trimerization of RANK and TRAF6, which leads to
the activation of NF-κB and mitogen-activated kinases
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© 2007 Nature Publishing Group
(MAPKs), including JUN N-terminal kinase (JNK)
and p38 (REF. 52). The essential role of NF-κB in osteo-
clastogenesis has been shown genetically53,54, but the
in vivo function of each MAPK remains to be elucidated.
The lysine-63-linked polyubiquitylation mediated by
the RING (really interesting new gene)-finger motif
of TRAF6 has been shown to be important for NF-κB
activation in other cell types55, but deletion analysis has
indicated that the RING-finger domain of TRAF6 is
dispensable for the formation of osteoclasts52. Therefore,
the importance of the ubiquitin-ligase activity of TRAF6
in osteoclastogenesis is yet to be established.
Although RANK activation is linked to the phos-
phorylation of DAP12 (also known as TYROBP and
KARAP) and Fc-receptor common γ-subunit (FcRγ),
as mentioned below, it is still not clear how RANK
alone among the TRAF6-binding receptors is able to
stimulate osteoclastogenesis so strongly. Additional
RANK-specific adaptor molecule(s) might exist and
enhance TRAF6 signalling50. For example, the molecular
scaffold GRB2-associated binding protein 2 (GAB2) has
been shown to be associated with RANK and to have
an important role in its signal transduction56. Signalling
crosstalk between RANKL and M-CSF, another essential
cytokine for osteoclast differentiation, might be crucially
important for osteoclastogenesis10, but it is only partially
characterized (FIG. 3). Similar to RANK, Toll-like recep-
tors (TLRs) also use TRAF6 as a crucial component of
their signalling cascade57, but how such receptor signal-
ling is able to bring about completely distinct outputs is
poorly understood.
RANK also activates the transcription-factor
complex, activator protein 1 (AP1), through induc-
tion of its component cFOS58, which has recently been
shown to be dependent on the activation of calcium/
calmodulin-dependent protein kinase type IV (CaMKIV)
and cyclic-AMP-responsive-element-binding protein
(CREB)59. Importantly, RANKL specifically and strongly
induces nuclear factor of activated T cells, cytoplasmic 1
(NFATc1), the master regulator of osteoclast differen-
tiation60, and this induction is dependent on both the
TRAF6–NF-κB and the cFOS pathways. The NFAT fam-
ily of transcription factors was originally discovered in
T cells, but they are involved in the regulation of various
biological systems61,62. Activation of NFAT is mediated
by a specific phosphatase, calcineurin, which is activ-
ated by calcium–calmodulin signalling. The essential
and sufficient role of the NFATc1 gene in osteoclas-
togenesis has been shown both in vitro and in vivo60,63.
The NFATc1 promoter contains NFAT binding sites and
NFATc1 specifically autoregulates its own promoter dur-
ing osteoclastogenesis and enables the robust induction
of NFATc1 (REF. 63). AP1 (containing cFOS) and continu-
ous activation of calcium signalling is crucial for this
auto-amplification60,64. NFATc1 regulates a number of
osteoclast-specific genes, such as cathepsin K, tartrate-
resistant acid phosphatase (TRAP), calcitonin receptor,
osteoclast-associated receptor (OSCAR) and β3-integrin,
in cooperation with other transcription factors such as
AP1, PU.1 and MITF60,65–67. A recent study indicated
that CREB activated by CaMKIV also cooperates with
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NFATc1 in the activation of osteoclast-specific genes59.
Compared with the wealth of information on the role
of RANKL in osteoclasts, it remains unclear whether
RANKL uses the same signalling mechanism when it
exerts its functions in the immune system40,41,44.
Interplay with other cytokine systems. Osteoclasts are
derived from the haematopoietic lineage and are there-
fore naturally influenced by cytokines that direct haema-
topoietic-cell differentiation. Crosstalk among cytokines
is a target of much interest for osteoimmunology, and

Osteoblast

RANKL Unknown
M-CSF
OPG Ig-like
RANK receptor cFMS

Osteoclast TRAF6 DAP12 or FcRγ

CD40L
IL-1 SYK PI3K GRB2 VAV3
cSRC
IFNγ cCBL
IKKs MAPKs PLCγ AKT ERK

Ca2+

IFNβ cFOS CREB CaMKIV Calcineurin Proliferation

and survival

TNF
NF-κB AP1 Cytoskeletal
reorganization
LPS ?

NFATc1 Auto-amplification Bone

• DC-STAMP resorption
AP1 Fusion
PU.1 • ATP6V0D2
NFATc1
MITF
CREB
• Cathepsin K
• MMP9
• ATP6I
Osteoclast • ClC7
differentiation
Figure 3 | Osteoimmunological interactions in osteoclasts and osteoblasts. The immune and skeletal systems
share cytokines, receptors, signalling molecules and transcription factors, all of which cooperatively regulate
osteoclasts and osteoblasts as well as their interactions. Osteoblasts regulate osteoclastogenesis through
receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL)–RANK (and its decoy receptor osteoprotegerin
(OPG)) interactions, macrophage colony-stimulating factor (M-CSF)–cFMS interactions and immunoglobulin
(Ig)-like receptors associated with immunoreceptor tyrosine-based activation motif (ITAM)-harbouring adaptor
molecules (such as DAP12 and Fc-receptor common γ-subunit (FcRγ), the ligands of which are not well
characterized). Although not depicted, semaphorin 6D and its receptor plexin A1, and ephrin receptor B4 and
ephrin B2 were newly identified as mediators of osteoblast–osteoclast interactions. There are extensive signalling
pathways in osteoclasts. RANK and Ig-like receptors stimulate downstream signalling cascades (such as tumour-
necrosis factor (TNF) receptor-associated factor 6 (TRAF6), NF-κB, mitogen-activated protein kinases (MAPKs),
activator protein 1 (AP1), calcineurin and nuclear factor of activated T cells, cytoplasmic 1 (NFATc1)), which are
influenced by a number of immunoregulatory molecules including CD40 ligand (CD40L), interleukin-1 (IL-1),
interferon-β (IFNβ), IFNγ, TNF and lipopolysaccharide (LPS). Dendritic-cell-specific transmembrane protein
(DC-STAMP) and ATP6V0D2 are necessary for the fusion of osteoclast precursor cells. Phosphoinositide 3-kinase
(PI3K)–AKT and GRB2–ERK (growth-factor-receptor-bound protein 2–extracellular-signal-regulated kinase)
pathways are important for the proliferation and survival of the osteoclast lineage, whereas VAV3, cSRC and
Casitas B-lineage lymphoma (cCBL) are included in the molecules required for cytoskeletal reorganization and
bone-resorbing osteoclasts. Osteoclast activity is dependent on acidifying proton pump ATP6I and chloride
channel ClC7, as well as matrix-degrading enzymes such as cathepsin K and matrix metalloproteinase 9 (MMP9).
The following molecules are known to be involved in both the bone system and the immune system: NF-κB,
RANKL, RANK, OPG, cFMS, M-CSF, Ig-like receptors, FcRγ, DAP12, TRAF6, MAPKs, AP1, calcineurin, NFATc1,
CD40L, IL-1, IFNγ, IFNβ, TNF, LPS, DC-STAMP, PI3K, AKT, ERK, VAV3, cSRC and cCBL. CaMKIV, calcium/
calmodulin-dependent protein kinase type IV; CREB, cyclic AMP responsive-element-binding protein;
PLC, phospholipase C; MITF, microphthalmia-associated transcription factor; IKK, inhibitor of NF-κB (IκB) kinase;
SYK, spleen tyrosine kinase.

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is of great clinical relevance. Inflammatory cytokines
that are mainly produced by macrophages, such as IL-1,
TNF and IL-6, promote osteoclastogenesis, and are also
called osteolytic cytokines on the basis of their bone-
resorbing effect in vivo24,25. IL-1 stimulates TRAF6 (and
therefore activates NF-κB and MAPKs) and synergizes
with RANKL to induce mature osteoclasts to carry out
bone-resorbing activity, but, interestingly, IL-1 alone
cannot induce differentiation, indicating that TRAF6
activation is not sufficient. IL-1 also indirectly facilitates
osteoclastogenesis by acting on the osteoblasts through
the induction of PGE2, and induces the expression of
RANKL25. TNF stimulates the activation of NF-κB
mainly through TRAF2. Although TNF alone cannot
induce osteoclastogenesis in vivo, nor can TNF over-
expression rescue the deficiency of RANKL68,69, it is
reported that TNF with transforming growth factor-β
(TGFβ) induces in vitro osteoclastogenesis even in the
absence of RANK or TRAF6 (REF. 70). These results
indicate that TNF has a pivotal role in the pathologi-
cal activation of osteoclasts that are associated with
inflammation.
Type I IFNs (that is, IFNα and IFNβ) are essential
for host defence against pathogens such as viruses.
The induction mechanism of type I IFNs in response to
pathogen-associated molecular patterns has been well
documented71, and recent studies on TLR signalling
have provided new insights into the mechanism and the
function of the IFN system57. Similar to TLRs, RANKL
induces the IFNB gene in osteoclast precursor cells, and
IFNβ functions as a negative-feedback regulator that
inhibits the differentiation of osteoclasts by interfer-
ing with the RANKL-induced expression of cFOS72.
The importance of type I IFNs in bone homeostasis was
underscored by the observation that mice deficient in the
type-I-IFN-receptor component IFNAR1 spontaneously
develop marked osteopaenia, accompanied by enhanced
osteoclastogenesis72.
As T-cell activation is often associated with
abnormal bone resorption, the regulation of bone
metabolism by T cells is one of the central subjects of
osteoimmunology 8,14,73. T cells express RANKL, but the
main T-cell cytokines such as IFNγ, IL-4 and IL-10 are
all inhibitory to in vitro osteoclastogenesis, and IL-12
and IL-18 also negatively affect osteoclastogenesis6,8,
indicating a complex mechanism working in vivo,
which will be discussed below.
Immune mediators in osteoimmunology
Transcription factors. NF-κB is a family of dimeric
trans cription factors including REL (cREL), RELA
(p65), RELB, NF-κB1 (p50) and NF-κB2 (p52, which
is processed from its precursor, p100)74. p50 and p52
function by heterodimerization with any of the three
REL proteins containing transcriptional activation
domains. Mice deficient in both p50 and p52 develop
osteopetrosis owing to a defect in osteoclast differentia-
tion, which indicates a crucial (but possibly overlapping)
Osteopaenia
function of p50 and p52 in osteoclastogenesis53,54. NF-κB
A decrease in bone mineral is required for NFATc1 induction, but it is not clear
density. whether NFATc1 is the exclusive transcriptional target
298 | APRIL 2007 | VOLUME 7
© 2007 Nature Publishing Group
of NF-κB during osteoclastogenesis63. Signals induced
by the pro-inflammatory cytokines probably converge at
the activation of NF-κB, which therefore has an integral
role in osteoimmunological interactions. The function
of classical and alternative NF-κB signalling pathways
has been studied using mice deficient in inhibitor of
NF-κB (IκB) kinases (IKKs)75 or NF-κB-inducing kinase
(NIK)76, but further studies will be needed to obtain a
complete understanding of their specific functions in
osteoimmunology.
As mentioned above, the AP1 component cFOS is
essential for the RANKL-mediated induction of NFATc1.
The AP1 transcription factor is a dimeric complex
composed of the FOS-family proteins (cFOS, FOSB,
FOS-related antigen 1 (FRA1) and FRA2), JUN-family
proteins (cJUN, JUNB and JUND) and activating trans-
cription factor (ATF)-family proteins58. The specific and
indispensable functions of AP1 transcription factors in
the regulation of osteoclasts and osteoblasts (for exam-
ple, the role of cFOS and FRA1 in bone resorption and
of FRA1 and ATF4 in bone formation) have been well
established by a series of studies from genetically modi-
fied mice58, but emerging evidence indicates that they
also have an unexpectedly interesting role in the immune
system (for example, the role of FOS in lipopolysaccha-
ride signalling)77,78, which indicates the importance of
AP1 in the osteoimmune system. Although the precise
composition of AP1 dimers is not well characterized in
the physiological context, a recent study showed that
an AP1 dimer composed of FOS and any JUN protein
induces osteoclastogenesis, but that FRA1 has different
partners79.
The NFAT transcription-factor family was originally
identified in T cells, and comprises five known members:
NFATc1 (also known as NFAT2), NFATc2 (also known
as NFAT1), NFATc3 (also known as NFAT4), NFATc4
(also known as NFAT3) and NFAT5 (REFS 61,62). This
family of transcription factors developed along with the
evolution of vertebrates, and is involved in the regulation
of various biological systems, such as the cardiovascular
and muscular systems, in addition to the bone system
and the immune system. As the activation of NFATc1–
NFATc4 is mediated by the phosphatase calcineurin,
which is activated by calcium–calmodulin signalling,
calcineurin inhibitors such as FK506 and cyclosporin A
strongly inhibit osteoclastogenesis60. The necessary and
sufficient role of the NFATc1 gene in osteoclastogen-
esis was established using a genetic approach, and the
robust induction of NFATc1 by an auto-amplification
mechanism is dependent on the epigenetically deter-
mined chromatin structure of the NFATc1 and NFATc2
promoters63. It is notable that NFATc1 has an exclusive
role in osteoclasts but that NFATc1 and NFATc2 have
a redundant role in T cells80. The importance of NFAT
in the regulation of bone homeostasis is also supported
by the recent findings that NFAT and calcineurin regu-
late osteoblast differentiation and bone formation81–83.
It has been shown that NFAT regulates bone formation
through interaction with OSTERIX81, but further stud-
ies are needed to clarify what activates calcineurin and
NFAT in osteoblasts.
www.nature.com/reviews/immunol

Nasu–Hakola disease
A rare autosomal-recessive
disease characterized by
systemic bone cysts and
psychotic symptoms similar to
dementia or schizophrenia
(mutations in DAP12 or
TREM2 genes are reported).
NATURE REVIEWS | IMMUNOLOGY
Inhibitor of DNA binding 2 (ID2) is a helix–loop–
helix protein, which often functions as a negative
regulator of helix–loop–helix transcription factors. Id2-
deficient mice have no lymph nodes or Peyer’s patches84,
and have a defect in mammary-gland formation as well
as a defective development of natural killer cells85. In this
respect, Id2–/– mice resemble RANKL–/– mice in many
ways, but, interestingly, osteoclastogenesis is enhanced
in Id2–/– cells86. ID2 therefore functions downstream of
RANKL, but, depending on the context, it can be both
a positive or negative regulator of RANKL signalling;
this indicates a unique osteoimmunological function for
this molecule.
Signal transducer and activator of transcription 1
(STAT1) has a crucial role in the immune system as a
mediator of signal transduction and a regulator of gene
transcription in both type I and II IFN systems87. In the
skeletal system, both types of IFN inhibit osteoclasto-
genesis through STAT1, but bone mass was increased
in STAT1-deficient mice, despite increased osteoclasto-
genesis. Subsequently, STAT1 was found to have a
unique, non-canonical function as a cytoplasmic attenu-
ator of RUNX2, a key transcription factor for osteoblast
differentiation88. Therefore, the loss of STAT1 results in
excessive RUNX2 activation and osteoblast differen-
tiation, thereby tipping the balance in favour of bone
formation over bone resorption. This is an interesting
example of an immunologically latent transcription fac-
tor having a distinct function in the skeletal system. As
expected, the suppressors of cytokine signalling (SOCS)
proteins, which are crucial regulators of IFN and STAT
signal transduction, are also involved in the diverse
regulatory mechanisms of osteoimmunology 89,90.
Schnurri-3 (SHN3), a zinc-finger protein, was first
identified as a DNA-binding protein involved in the
regulation of V(D)J recombination of immunoglobulin
genes. However, SHN3 has been shown to have an
important role in the control of bone formation through
proteolytic degradation of RUNX2, to which the activ-
ity of WWP1 (WW domain-containing E3 ubiquitin
protein ligase 1) might also contribute91.
Therefore, accumulating evidence indicates that a
great number of transcriptional regulators are shared
by the immune and the bone systems, and they con-
trol not only osteoclasts but also osteoblasts (FIG. 3).
Osteoblast-mediated bone formation is also affected
by soluble factors such as cytokines in the immune sys-
tem, including TNF, IL-1 and IL-4 (REF. 6); osteoblasts
are therefore influenced by the immune cells, although
the physiological and pathological significance and the
molecular mechanisms are less well understood than in
osteoclasts.
Immunoreceptors and co-stimulation. RANK and
cFMS were thought to be necessary and sufficient for
osteoclastogenesis24, but this was only based on the
observation that the addition of RANKL and M-CSF
is sufficient to induce osteoclast formation in a culture
system. Genome-wide screening and gene-disruption
studies have shed light on hitherto-unknown functions
of immunological receptors, such as osteoclast-associated
© 2007 Nature Publishing Group
REVIEWS
receptor (OSCAR; an immunoglobulin-like receptor)92,
DC-specific transmembrane protein (DC-STAMP;
a seven-transmembrane-domain-containing receptor
that mediates cell–cell fusion of osteoclasts)93,94 and
B7-H3 (a member of the B7 superfamily; also known as
CD276)95, in addition to those involved in axon guid-
ance, including the ephrin96 and semaphorin receptors97.
In vitro studies also have shown that osteoclast-inhibitory
lectin (OCIL) and 4-1BB (also known as CD137) might
be involved in the regulation of osteoclastogenesis. These
findings indicate that osteoclast differentiation is regu-
lated by additional receptor systems that cooperate with
RANK and cFMS, and many of them are involved in the
interaction between the osteoblast and osteoclast line-
ages. Therefore, an increasing number of ligand–receptor
systems originally identified in the immune system have
also been found to be functional in the skeletal system
(FIG. 3; TABLE 1; Supplementary information S1 (table)).
FcRγ and DAP12 are adaptor molecules that associate
with immunoglobulin-like receptors, classically helping
these receptors to express themselves on the membrane,
and transduce signals through the immunoreceptor
tyrosine-based activation motif (ITAM) in natural
killer and myeloid cells98. An osteopetrotic phenotype
observed in mice deficient in both FcRγ and DAP12 led
to the designation of immunoglobulin-like receptors as
crucial co-stimulatory molecules for RANK99,100. The
immunoglobulin-like receptors identified in osteoclast-
precursor cells include OSCAR, triggering receptor
expressed in myeloid cells 2 (TREM2), signal-regulatory
protein β1 (SIRPβ1) and paired immunoglobulin-like
receptor A (PIRA), although the ligands and function of
each of these receptors remain to be elucidated. ITAM-
mediated signals cooperate with RANK to stimulate
calcium signalling through ITAM phosphorylation and
the resulting activation of spleen tyrosine kinase (SYK)
and phospholipase Cγ (PLCγ)101. As this pathway is
crucial for the robust induction of NFATc1 that leads
to osteoclastogenesis, but because ITAM signals alone
cannot induce osteoclastogenesis, these signals should
be called co-stimulatory signals for RANK5,99.
The role of the immunoreceptor tyrosine-based
inhibitory motif (ITIM) in osteoclast differentia-
tion remains to be elucidated, but osteoclastogenesis
is enhanced in mice lacking phosphatases such as
SH2-domain-containing protein tyrosine phosphatase 1
(SHP1)102,103 or SH2-domain-containing inositol-5-
phosphatase 1 (SHIP1)104, which counterbalance the
ITAM signal in the immune system. The importance
of the ITAM-harbouring adaptors and the recep-
tors associated with them in bone metabolism is also
underscored by reports that mutations in the DAP12
and TREM2 genes cause skeletal and psychotic abnor-
malities that are collectively known as Nasu–Hakola
disease98. The expression of semaphorins, which are
axon-guidance molecules and immunoregulators, has
been observed in bone cells, but it has recently been
shown that semaphorin 6D and its receptor plexin-A1
might have an important role in the activation of the
DAP12-mediated ITAM signal through the interactions
among plexin-A1, DAP12 and TREM2 (REF. 97).
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Table 2 | Cytokines functioning in the regulation of osteoclast differentiation by T cells

Cytokine Effects on Main producer cells Main target cells in the Functions in the context of osteoimmunology
osteoclastogenesis regulation of osteoclasts
IFNγ Inhibition TH1 cells and NK cells Osteoclast precursor cells Cellular immunity; RANKL signalling inhibition
IL-4 Inhibition TH2 cells and NKT cells Osteoclast precursor cells Humoral immunity; RANKL signalling inhibition
IL-6 Activation TH2 cells and DCs Mesenchymal cells and Inflammatory; RANKL induction on mesenchymal
T cells cells; TH17-cell differentiation
IL-10 Inhibition TH2 cells Osteoclast precursor cells Anti-inflammatory; RANKL signalling inhibition
GM-CSF Inhibition TH1 cells Osteoclast precursor cells Granulocyte differentiation; RANKL signalling
inhibition
IL-12 Inhibition Macrophages and DCs T cells TH1-cell differentiation; IFNγ and GM-CSF
induction
IL-17 Activation TH17 cells and memory Mesenchymal cells Inflammatory; RANKL induction on mesenchymal
T cells cells
IL-18 Inhibition Macrophages and DCs T cells TH1-cell differentiation, IFNγ induction
RANKL Activation T cells and Osteoclast precursor cells Osteoclast differentiation induction
mesenchymal cells
(osteoblasts)
TNF Activation Macrophages and TH1 Osteoclast precursor cells Inflammatory; RANKL induction on mesenchymal
cells and mesenchymal cells cells; synergy with RANKL
DC, dendritic cell; GM-CSF, granulocyte macrophage colony-stimulating factor; IFNγ, interferon-γ; IL, interleukin; NK, natural killer; NKT, natural killer T; RANKL,
receptor activator of nuclear factor-κB ligand; TH, T helper; TNF, tumour-necrosis factor.

Cellular interactions in the osteoimmune system
Lymphocyte regulation of osteoclasts. Activation of the
immune system is essential for host defence against
pathogens, but aberrant and/or prolonged activation
under certain pathological conditions results in tis-
sue damage owing to the activation of effector cells.
In autoimmune arthritis, it has long been a challeng-
ing question as to how the abnormal T-cell activa-
tion (characterized by infiltration of CD4+ T cells)
mechanistically induces bone damage8,9. Researchers
had already observed osteoclast-like cells at the bone-
destruction site in the early 1980s (REF. 105), but the
importance of osteoclasts has just recently come into
general acceptance because of the therapeutic efficacy
of osteoclast-targeted therapies14,106 and the protec-
tion of osteoclast-deficient mice from inflammatory
bone loss107,108. It remains unclear whether osteoclasts
under physiological and inflammatory conditions have
distinct characteristics, but osteoclasts are partly resist-
ant to apoptosis induced by bisphosphonates in the
presence of inflammatory cytokines.
As RANKL is expressed in activated T cells, T cells
might have the capacity to induce osteoclast differentia-
tion by directly acting on osteoclast-precursor cells14,109.
However, the IFNγ produced by T cells potently sup-
presses RANKL signalling through downregulation of
TRAF6 (REF. 73). T cells also secrete various cytokines
such as IL-4 and IL-17 (REF. 110) (TABLE 2), so the effects
of T cells on osteoclastogenesis should be dependent
on the balance between positive and negative factors
expressed by the T cells. As the well-known effector
CD4+ T helper (TH)-cell subsets TH1 and TH2 produce
IFNγ and IL-4, respectively, both of which are anti-
osteoclastogenic, it has been a paradox that activated
CD4+ T cells in arthritis enhance osteoclastogenesis in
the presence of these cytokines.
It is worthwhile to define what we believe to be a very
rare but pathologically important TH-cell subset respon-
sible for abnormal bone resorption as osteoclastogenic
TH cells. Previous investigations in our laboratory and
other studies on synovial T cells in rheumatoid arthritis
clarified the characteristics of osteoclastogenic TH cells
in autoimmune arthritis 8,9. First, osteoclastogenic
TH cells do not produce a large amount of IFNγ. Second,
they trigger local inflammation and the production of
inflammatory cytokines, including TNF, that induce
RANKL expression on synovial fibroblasts. Third, osteo-
clastogenic TH cells express RANKL and might directly
participate in accelerated osteoclastogenesis. Because
these TH cells have such osteoclastogenic characteristics,
they can tip the balance in favour of osteoclastogenesis
in various aspects. Although autoimmune arthritis has
been traditionally categorized as a TH1-type disease,
TH1 cells do not have such characteristics, indicating that
the osteoclastogenic TH cells might belong to an as-yet
unknown subset.
Recent data from our laboratory indicate that an
IL-17-producing TH-cell subset (TH17 cells) represents
the long-sought-after osteoclastogenic TH-cell subset,
fulfilling all the criteria mentioned above111. Therefore,
the infiltration of TH17 cells into the inflammatory lesion
links the abnormal T-cell response to bone damage
(FIG. 4), and the pathogenesis of autoimmune arthritis
should be reconsidered in the context of a TH17-type
disease. Clearly, this subset will be an auspicious target of
future therapy, and cytokines related to TH17-cell differ-
entiation and expansion, such as IL-6, TGFβ and IL-23,
will be of great clinical importance.
Compared with the established pathological
role of T cells in arthritis, the role of T cells in non-
inflammatory metabolic bone diseases such as postmeno-
pausal osteoporosis has recently been proposed112 but is

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Rheumatoid joint Normal joint

Inflamed
synovium
Bone

Osteoclastogenesis
and bone destruction
Synovial Osteoclast
membrane

Cartilage
Osteoclast
precursor cell
Synovial
macrophage
Inflammatory
Blood cytokines such
vessel as TNF, IL-1 and IL-6

IL-17
Increased
RANKL
Synovial fibroblast
Synovial
T cell
(TH17 cell)

Figure 4 | How T cells induce osteoclastogenesis in autoimmune arthritis. In rheumatoid arthritis, inflammatory
synovium invades and destroys bone; this is mediated by osteoclasts that are induced by receptor activator of nuclear
factor-κB ligand (RANKL). Cells in the synovium include synovial macrophages and fibroblasts in addition to the dendritic
cells, plasma cells, endothelial cells and infiltrating T cells. Although CD4+ T-cell infiltration is a hallmark of the
pathogenesis of arthritis, the link between T cells and the activation of osteoclast-mediated bone resorption has only
recently been shown: interleukin-17 (IL-17)-producing T helper cells (TH17 cells) are the only osteoclastogenic TH-cell
subset characterized so far. TH17 cells do not produce interferon-γ (IFNγ), which suppresses RANKL signalling, but secrete
a huge amount of IL-17 that induces RANKL on synovial fibroblasts. IL-17 also stimulates the local inflammation and
activates synovial macrophages to secrete pro-inflammatory cytokines such as tumour-necrosis factor (TNF), IL-1 and IL-6.
These cytokines activate osteoclastogenesis by either directly acting on osteoclast precursor cells or inducing RANKL on
synovial fibroblasts. TH17 cells also express RANKL on their membrane, which partly contributes to the enhanced
osteoclastogenesis.

Trabecular bone
A spongy and low-density type
of osseous tissue with high
surface area, which fills up the
inner cavity of long bones and
vertebrae.
not yet recognized by immunologists. The possibil-
ity that oestrogen regulates T-cell immune responses
and that T-cell-mediated autoimmunity is involved
in postmenopausal osteoporosis is intriguing, and
further points to the notion of an intricate interplay
between the immune and skeletal systems, but this
concept is still highly controversial113 and will not be
proved until the autoantigen that causes osteoporosis
is identified114.
Osteoblasts as a stem-cell niche. Osteoimmunology
is in the process of extending beyond the function of
immune mediators in bone cells — increasing atten-
tion is currently being given to the regulation of HSCs
by bone cells. The role of osteoblasts in haematopoiesis
was proposed in a previous study, in which impaired
haematopoiesis was observed after the chemical abla-
tion of osteoblasts115. HSCs interact with specialized
microenvironments, known as stem-cell niches, to
maintain the ability of self-renewal and pluripotency.
Osteoblasts on the trabecular bone surface have emerged
as a crucial component of the niche, and the interaction
between osteoblasts and HSCs is mediated by molecular
interactions, such as N-cadherin–β-catenin, Jagged–
Notch1 and angiopoietin-1–tyrosine kinase receptor 2
interactions15,16,18. It is possible that the osteoblast and
niche functions are under the control of bi-potential
regulators such as WNT 116. The CXCL12–CXCR4
(CXC-chemokine ligand 12 (also known as SDF1)–
CXC-chemokine receptor 4) system is also involved in
the colonization of bone marrow by HSCs and in their
retention in the bone marrow, but the localization of
CXCL12-expressing cells is not consistent with that
of osteoblasts on the trabecular bone surface117.
Therefore, the detailed localization and characteriza-
tion of cells representing the stem-cell niche in the bone
marrow remain to be clarified in the future. As it is
unclear whether the bone-forming capacity is related
to the function required for the niche, it is necessary to
carefully reconsider the definition of osteoblasts. More
recently, osteoclasts have also been indicated to be
involved in the mobilization of HSCs17, further support-
ing the intimate relationship between the haematopoietic
and skeletal systems.

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Clinical implications osteoclastogenesis by suppressing the induction of

A detailed osteoimmunological understanding of the
pathogenesis of bone destruction in many contexts
will lead to novel strategies for the treatment of various
diseases, including rheumatoid arthritis, periodontal dis-
ease, Paget’s disease, osteoporosis, osteoarthritis, multiple
myeloma and metastatic bone tumours. Rheumatologists
are now aware of the remarkable impact of TNF-specific
antibody therapy on the treatment of rheumatoid arthri-
tis, and other cytokines will soon be targeted by similar
strategies using biological agents19. The action of TNF
and other inflammatory cytokines is not limited to the
induction of local inflammation, but is directly and indi-
rectly involved in the activation of osteoclasts, as men-
tioned above. Such osteoimmunological pleiotropy might
explain the dramatic efficacy of the biological agent to
prevent or even ameliorate bone destruction. In addition,
the efficacy of a RANKL-specific antibody for postmeno-
pausal osteoporosis and rheumatoid arthritis in clinical
trials has been reported118,119, and its apparent preventive
effect on bone metastasis is enormously promising 46.
Interestingly, severe adverse effects of RANKL inhibi-
tion on the immune system have never been reported.
The clinical relevance of newly recognized cytokines
such as IL-17 and IL-23 has yet to be established in
humans, but IL-6 inhibition, which is also under
clinical trial with successful results, might have a dual
impact on TH17-mediated immune responses and
bone120. Although it is difficult to specifically target
transcription factors and signalling molecules in drug
treatment, some of the anti-rheumatic drugs inhibit
NFATc1 (REF. 121). Therefore, the osteoimmunological
perspective has enabled us to gain profound insights into
the understanding of the mode of action of therapeutic
drugs as well as a novel strategy for drug design.
Concluding remarks and future perspectives
The bone system and the immune system share an abun-
dance of molecules and regulatory mechanisms, and this,
together with the importance of the interactions between
the two systems might have resulted in the emergence
of the field of osteoimmunology, but more attention
should be paid to the differences in the future: how are
distinct functions achieved through similar mechanisms?
Similarly, genetically modified mice deficient in a mol-
ecule originally characterized in one system should be
analysed in another system to clarify the functions in the
context of the osteoimmune system. This will surely lead
to an understanding of the molecular basis for the cell-
lineage specification and, perhaps more importantly,
cell-type-specific treatment despite the similarity of
the two systems. The novel functions of bone cells in the
regulation of cells outside the bone will have an impact
on many genres of biomedical studies. For example, the
crucial function of bone cells in the control of HSCs might
provide new methods to modulate the HSC mobilization
through bone cells. Therefore, there is reason to believe
that both clinical and non-clinical researchers will benefit
from the emerging insights that are leading to an inte-
grated understanding of the osteoimmune system and its
complex interactions.

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Acknowledgements
We thank Y. Choi, G. Karsenty, N. Takahashi, K. Matsuo,
T. Nakashima, M. Asagiri, T. Koga and M. Shinohara for
critical reading of the manuscript and fruitful discussion.
The work was supported in part by Grants-in-Aid for Creative
Scientific Research from Japan Society for the Promotion of
Science, SORST program of Japan Science and Technology
Agency, Grants-in-Aid for the 21st century COE program
and Genome Network Project from Ministry of Education,
Culture, Sports, Science, and Technology of Japan (MEXT),
Grants-in-Aid for Scientific Research from MEXT, and Health
Sciences Research Grants from the Ministry of Health,
Labour and Welfare of Japan.
Competing interests statement
The authors declare no competing financial interests.
DATABASES
The following terms in this article are linked online to:
Entrez Gene:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene
DAP12 | IL-1 | M-CSF | NF-κB | OSTERIX | RANKL | RUNX2
FURTHER INFORMATION
Hiroshi Takayanagi’s homepage:
http://osteoimmunology.com/
SUPPLEMENTARY INFORMATION
See online article: S1 (table)
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