RANK

8 Pages·0.264 MB·English

by  Boyle W.J.

RANK
William J. Boyle*
Department of Cell Biology, Amgen, Inc., One Amgen Center Drive, Thousand Oaks,
CA 91320-1799, USA
*corresponding author tel: [phone], fax: [phone], e-mail: [email protected]
DOI: 10.1006/rwcy.2000.16008.
SUMMARY involvedinregulatingdendriticcellfunction(s)during
adaptive immune responses. Functional analysis of
the receptor in mammalian cell lines indicated that,
RANK is a novel member of the TNFR superfamily
like other TNFR family members, RANK was
that is capable of activating the NF(cid:20)B and JNK
capable of activating the transcription factor NF(cid:20)B.
pathwaysduringcellsurvival.Itwasoriginallycloned
A ligand for RANK (RANKL) was expression
from a dendritic cell cDNA library suggesting a role
cloned from a T cell line library using a soluble
in modulating dendritic cell function(s) during regu-
receptor fusion dimer. RANK was also identified by
lation of immune responses. RANK is one of the
twoindependentgroupsasthereceptorthatregulated
largestTNFR-relatedproteins,characterizedashaving
osteoclastogenesis mediated by osteoclast differentia-
four cysteine-rich repeats motifs in its extracellular
tion factor (ODF) or osteoprotegerin ligand (OPGL)
domain, and a long intracellular signaling domain.
(Nakagawa et al., 1998; Hsu et al., 1999). Interest-
The intracellular domain is now known to bind to
ingly, RANKL/ODF/OPGL/TRANCE was also
members of the TRAF family of signal transducers,
identified as a T cell protein whose expression was
which mediate the activation of NF(cid:20)B and JNK
controlled by calcineurin-regulated transcription fac-
following ligand binding.
tors during activation (Wong et al., 1997).
RANK is expressed at very high levels on osteo-
Thus, the various experimental approaches used to
clast precursors, and is the hematopoietic cell surface
identify both RANK and RANKL strongly impli-
protein that mediates the osteoclastogenic effects of
cated a role for this receptor in regulating T cell and
RANKL. Since RANKL induction by calciotropic
dendritic cell interactions. In addition, cell biological
hormones and pro-resorptive cytokines is known to
and molecular genetic analysis in mouse has revealed
regulatebonedensityandcalciummetabolism,RANK
an essential function in regulating osteoclast differ-
is implicatedasthe osteoclast receptor thatintegrates
entiation and activation during bone remodeling and
these humoral signals during physiologic conditions
metabolism (see Suda et al., 1999, for review).
and during disease.
Alternative names
BACKGROUND
ODFR, osteoclast differentiation factor receptor
Discovery
(Nakagawa et al., 1999).
ODAR, osteoclast differentiation and activation
The TNFR-related protein RANK (receptor activa-
receptor (Hsu et al., 1999).
tor of NF(cid:20)B) was first identified as an interesting
TRANCE-R,TRANCEreceptor(Wongetal.,1998).
EST sequence obtained from a dendritic cell cDNA
library(Andersonetal.,1997).Itisnowknowntobe
Structure
an important component of the OPG–RANKL–
RANK axis involved in regulating bone and immune
homeostasis. The full-length cDNA encoded a novel The human RANK polypeptide is a 616 amino acid
TNFR-related protein, and was predicted to be type I transmembrane protein that is functionally
1692 William J. Boyle
divided into two regions (Anderson et al., 1997). The GENE
N-terminal region of the protein is the extracellular
ligand-bindingdomainoftheproteinthatisdisplayed
Accession numbers
on the cell surface. The C-terminal region of the
receptor is the cytoplasmic, signal-transducing por-
Human and mouse cDNA sequences:
tion that effects cellular metabolic functions in
AF018253
response to activation by ligand.
AF019046
AF019047
AF019048
Main activities and
pathophysiological roles
Sequence
Activation of RANK by overexpression in trans-
See Figure 1.
fected cells, or by treatment of receptor-bearing cells
in vitro with soluble RANKL (a.k.a. TRANCE/
ODF/OPGL), has been shown to stimulate signal PROTEIN
transduction leading to the activation of NF(cid:20)B
(Andersonetal.,1997;Darneyetal.,1999,Hsuetal.,
Accession numbers
1999).Themechanismforthisisdescribedbelow,but
isknowntoinvolvecytoplasmicfactorsthatbelongto
Human RANK protein: AF018253
the TRAF family of proteins. RANK activation has
also been shown to rapidly stimulate Jun N-terminal
kinase (JNK/SPK), leading to activation of AP-1 Sequence
related transcription factors (Wong et al., 1997;
Galibert et al., 1998; Hsu et al., 1999). Our current
See Figure 2.
view of RANK is that it is involved in both immune
and bone homeostasis.
Description of protein
RANK was identified as a dendritic surface
receptor, indicating a potential role in modulating
dendritic cell differentiation and survival. Soluble Human RANK is a TNFR-related, type I transmem-
RANKL can act as a costimulatory factor during brane protein of 616 amino acid residues (Figure 3),
antigenpresentationduringinvitroculture(Anderson whereas the mouse polypeptide is 625 residues. A
et al., 1997), and impacts the survival of dendritic hydrophobicsignal peptideof29aminoacidslocated
cells during in vitro culture (Wong et al., 1997). The at the extreme N-terminus, and is removed during
effects mediated by RANKL on dendritic cell func- synthesis. The C-terminal extracellular domain is
tion are dependent on native folding of this cytokine, composedoffourtandemcysteine-richpseudorepeat
and can be blocked by the addition of a soluble sequences (I–IV) that are characteristic of this family
RANK-Ig fusion protein. (Smith et al., 1994), followed by a stalk of about 17
RANK has also been identified as the intrinsic residues.Thepseudorepeatsequencesareinvolvedin
hematopoietic cell surface determinant required for ligand binding, and are most closely related to
the differentiation and activation of the osteoclast domains I–IV of CD40, a TNFR-related protein
(Nakagawa et al., 1998; Hsu et al., 1999). RANK is important for B cell maturation and activation.
expressed at very high levels on osteoclast progenitor A hydrophobic sequence of about 23 amino acids
cells(Laceyetal.,1998;Hsuetal.,1999).Additionof forms a membrane-spanning domain and helps to
soluble RANKL to bone marrow cultures in the define the extracellular domain of this receptor. The
presence of CSF-1 (M-CSF) stimulates osteoclasto- C-terminal 383 amino acid residues forms the cyto-
genesis and the activation of mature osteoclasts to plasmic region or RANK, and is one of the longest
resorb bone via binding to RANK (Hsu et al., 1999; cytoplasmic domains of receptors in this class. This
Burgess et al., 1999). These effects can be blocked by region of the protein has been shown to bind to a
the addition of either OPG or soluble RANK-Ig. class of cytoplasmic tumor necrosis factor receptor-
Recombinant soluble RANK-Ig can block osteo- associated factors (TRAFs), which are involved in
clastogenesis and activation when administered to ligand-induced signal transduction leading to the
mice, leading to increases in bone mass (Hsu et al., activationofNF(cid:20)B and JNK/SAPKpathways(Arch
1999). et al., 1998).
RANK 1693
Figure 1 Nucleotide sequence for human RANK.
Figure2 AminoacidsequenceforhumanRANKprotein.Thehydrophobic
signal peptide and transmembrane domain are underlined.
Relevant homologies and species
compared (Anderson et al., 1997). The human and
differences
mouse proteins are about 85% identical, with se-
quencegapsduetothefactthatthemurineproteinis
The mouse and human RANK cDNAs have been longer. All of the cysteine residues located in the full-
cloned and sequenced, and their protein products lengthmatureproteins(residues29–194)areconserved
1694 William J. Boyle
Figure3 TheprimarystructureoftheRANKpolypeptide.Theextracellulardomaincontainsa
shorthydrophobicsignalpeptide(blackbox),fourtandemcysteine-richpseudorepeatsequences
(I–IV), and a short stock region. A hydrophobic transmembrane domain anchors the RANK
protein to the cell membrane. The cytoplasmic region contains at least three functional TRAF-
binding sites indicated by the hatched bars. The amino acid coordinates for the various RANK
structural features are listed below.
and in identical positions. RANK is most closely Table 1 Cell types and tissues expressing the receptor
related to the TNFR-related protein CD40, and is
about 40% similar in the ligand-binding domain. Organs and Cartilaginous bone primordia
tissues during fetal development
Intestinal epithelium
Affinity for ligand(s)
Kidney
Liver
Various lines of evidence suggest that RANKL is the
Bone and growth plate cartilage
major, if not sole, ligand for RANK. Mice in which
eithertheRANK(Dougalletal.,1999;Lietal.,2000) Lymph node
or RANKL (OPGL) (Kong et al., 1999a) genes have Spleen
been disrupted by homologous recombination have
Thymus
nearidenticalphenotypeswithrespecttobonemetab-
Heart
olism and lymph node organogenesis. Biochemical
analysis of surface proteins found on primary Cell types Hypertrophic chondrocytes
marrow-derived osteoclast progenitors indicates that Osteoclast progenitors
RANK is the only protein present on these cells that
Myeloid precursors
interacts with soluble RANKL (Hsu et al., 1999;
B cells, activated
Nakagawa et al., 1998). Soluble RANK-Ig fusion
protein (sRANK-Ig) and RANKL binding coeffi- Intestinal epithelium (small and large)
cientshavebeendeterminedbyBIAcoreandsolution Dendritic cells
binding,andfoundtobeintherangeof(cid:24)3(cid:2)10(cid:255)9M
Foreskin fibroblasts
(Hsuetal.,1999).Osteoprotegerin,asecretedRANKL
Cell lines RAW 264.7 (murine macrophage)
neutralizingreceptor, bindsto RANKLwith approx-
imately 10–100 times higher affinity ((cid:24)3(cid:255)10(cid:2)10(cid:255)11) KG-1 (human myeloid leukemia)
using these same assays. In support of this difference K562 (human erythroleukemia)
in affinity for the same ligand, OPG and sRANK-Ig
LIM 1863 (human colorectal carcinoma)
have similar differences in EC values for neutraliz-
50 MP-1 (human lymphoblastoid)
ing RANKL-induced osteoclastogenesis in vitro and
in vivo (Hsu et al., 1999). A-172 (human glioblastoma)
W1-26 (human lung fibroblast,
SV-40 transformed)
Cell types and tissues expressing
the receptor
See Table 1.
receptors, regulation of its activity is via ligand bind-
ing, and not necessarily at the transcriptional level.
Regulation of receptor expression
Cell types bearing this receptor are likely to acquire
expression during development and lineage alloca-
Little is actually known about the regulation of tion, such as in the osteoclast. RANK expression is
RANK expression in cells and tissues. Like many detected early during hematopoietic development
RANK 1695
from stem cells, and is found on early myeloblast cell metabolic processes via the activation of signal
lines such as KG-1 and K562 (Anderson et al., 1997; transducing cytoplasmic factors. RANK contains no
Lacey et al., 1998). RANK expression on the surface death domain motifs, and is not believed to play a
of hematopoietic precursor cells is the key deter- role in mediating apoptosis. In contrast, its structure
minant that typifies the osteoclast progenitor (Lacey ismorerelatedtoreceptorssuchasCD40,whichtend
etal.,1998;Hsuetal.,1999;Lietal.,2000).Anderson to promote cell survival and can stimulate differ-
et al. (1997) have identified cells that express high entiation. RANK was first characterized as a den-
levels of RANK mRNA, but do not express surface dritic cell surface protein proposed to function in
protein that crossreacts with anti-RANK antibodies, T cell and dendritic cell interactions during the
suggesting that posttranscriptional mechanisms reg- immune response. Wong et al. (1997) first reported
ulate surface localization of the receptor. Interest- that RANKL (TRANCE) could stimulate JNK/
ingly, activation by the cytokines IL-4 and TGF(cid:12)1 SAPKactivityintreatedcells,suggestingthatRANK
induce surface expression in these cells. was involved in stimulating cell activation mecha-
Osteoclast progenitors express very high levels of nisms. RANK itself was first characterized as a
RANK mRNA and surface receptor (Lacey et al., receptor-like protein capable of stimulating the tran-
1998; Hsu et al., 1999). During differentiation into scription factor NF(cid:20)B (Anderson et al., 1997). These
mature osteoclasts, RANK expression is downregu- datasuggestedthattwomajorcellularsignalingpath-
lated,althoughthereceptorisstillpresentandableto ways, JNK/SAPK and NF(cid:20)B, were regulated by
bind and respond to soluble RANKL (Burgess et al., activation of this receptor. Activation of RANK on
1999). osteoclast progenitor cells leads to the rapid stimula-
The mouse RANK transcript is expressed in the tion of JNK activity, and subsequently the induction
cartilaginous primordia of bone during embryonic of osteoclast-specific gene expression (Lacey et al.,
development, then later is expressed in the intestine, 1998; Hsu et al., 1999). Apparently, NF(cid:20)B is not
kidney, lung, and bone (Hsu et al., 1999). In situ activated during this process, but is already consti-
hybridization of embryonic and adult mouse bone tutively active at this stage of osteoclast precursor
indicates that RANK is expressed at sites of robust development. However, RANK present on mature
bone resorption and remodeling, such as in the osteoclasts respondstoligand treatmentbyinduction
growth plate cartilage region. In addition, RANK is of both JNK/SAPK and NF(cid:20)B activity, and these
expressedonhypertrophicchondrocytes,suggestinga functions both appear to be critical for osteoclast
roleinregulatinggrowthplatephysiology.Insupport survival and activation (Jimi et al., 1999).
of this concept, mice deficient in RANKL have The RANK cytoplasmic domain is about 383
developmental alterations in chondrocyte develop- amino acids in, and contains no obvious structural
ment, and have abnormal-looking growth plate features that imply a signaling mechanism. Other
cartilage (Kong et al., 1999a). members of the TNFR family are known to mediate
signal transduction via cytoplasmic factors belong to
the TRAF family of proteins (Arch et al., 1998).
Release of soluble receptors
RANK presumably mediates the activation of the
transcription factor NF(cid:20)B and JNK/SAPK activity
The mature RANK polypeptide has not been shown bycouplingwiththisclassofcytoplasmicfactors.The
tobecleavedfromthecellsurface,releasingasoluble TRAFfamilymembers1,2,3,5,and6wereallfound
ectodomain. However, as mentioned above, post- to interact with the cytoplasmic domain of RANK
transcriptional regulation of RANK is thought to in vitro (Galibert et al., 1998; Wong et al., 1998;
occur, and this could involve cleavage of the extra- Darney et al., 1999; Hsu et al., 1999) (Figure 4).
cellular domain. If this occurs, this could provide a Putative TRAF-binding sites have been found at
mechanism for modulating the effects of RANKL several locations within the RANK cytoplasmic
during immune and bone homeostasis. Osteopro- domain of about 5–6 amino acids in length (Darney
tegerin is a known secreted inhibitor of RANKL. et al., 1999). In cultured cells, TRAF2, 5, and 6
interactions with the RANK cytoplasmic domain
havebeendetected(Galibertetal.,1998;Darneyetal.,
SIGNAL TRANSDUCTION
1999; Hsu et al., 1999). Both TRAF2 and TRAF5
have been shown to bind within the same sites at the
The primary structure of RANK suggests that it veryC-terminusoftheprotein,whileTRAF6bindsto
mediatestheeffectsofRANKLinafashionsimilarto a two potential juxtaposed sites lying between amino
that of other TNRF-related proteins when they acid residues 340 to 358 (Galibert et al., 1998; Hsu
engage their cognate ligands: induction of cellular et al., 1999). Yeast two-hybrid interaction screening
1696 William J. Boyle
Figure 4 RANK signaling failureintootheruption),confirmingabiologicalrole
pathway. Illustration of the for this protein in osteoclast function and in bone
RANKtypeItransmembrane metabolism (Lomaga et al., 1999). In vivo, mature
protein on the cell surface in
osteoclasts are observed, but ultrastructural analysis
relationtocytoplasmicfactors
indicates that there is a defect in the ability of osteo-
involved in RANK signal
clastslackingTRAF6toadheretobonesurfaces,and
transduction. RANKL bind-
formation of normal resorption lacunae.
ing to RANK induces the
aggregation of TRAF2, 5,
and 6, and subsequently the
activationofNF(cid:20)BandJNK/ DOWNSTREAM GENE
SAPK. TRAF6 has been
ACTIVATION
implicatedasthemajorsignal
transducing TRAF protein
involved in regulating osteo- Transcription factors activated
clastogenesis.DuringRANK-
L-induced osteoclastogenesis,
Activation of RANK on osteoclast progenitor cells
JNK/SAPK is rapidly in-
leads to the rapid stimulation of JNK activity, and
duced, followed by induction
of osteoclast specific gene subsequently the expression of several genes that
expression (TRAP, cathepsin typify the osteoclast lineage. These genes include
K, calcitonin receptor, and tartrate-resistant acid phosphatase (TRAP), the
(cid:11)v(cid:12)3). calcitonin receptor, cathepsin K, the integrin (cid:11)v(cid:12)3,
andthec-srcproto-oncogene(Laceyetal.,1998;Hsu
et al., 1999). The promoter regions of these genes are
currently being characterized to identify the tran-
scription factors that mediate RANK regulation of
osteoclast development.
BIOLOGICAL CONSEQUENCES
OF ACTIVATING OR INHIBITING
RECEPTOR AND
PATHOPHYSIOLOGY
Unique biological effects of
activating the receptors
The following in vitro and in vivo biological effects
havebeenreportedasadirectorindirectconsequence
of activating RANK on receptor-bearing cells
following stimulation with RANKL:
of osteoclast precursor cDNA libraries identified (cid:15) Activationofosteoclastdifferentiation(Laceyetal.,
TRAF6 as the major TRAF-related protein that 1998; Nakagawa et al., 1998; Hsu et al., 1999).
binds to the RANK cytoplasmic domain in these (cid:15) Induction of osteoclast-specific gene expression
cells. This same internal region of the RANK (Lacey et al., 1998; Hsu et al., 1999).
cytoplasmic domain was also found to be required (cid:15) Induction of mature osteoclast survival (Jimi et al.,
for the induction of NF(cid:20)B and JNK activity in 1999).
osteoclast precursors during the induction of osteo- (cid:15) Activation of osteoclast-mediated bone resorption
clast-specificgeneexpression,suggestingthatTRAF6 (Lacey et al., 1998; Burgess et al., 1999).
is an important signal transducer during induction of (cid:15) Regulation of lymph node organogenesis (Kong
osteoclastogenesis(Hsuetal.,1999).Micedeficientin et al., 1999a; Dougall et al., 1999; Li et al., 2000).
TRAF6 have recently been analyzed, and found to (cid:15) Stimulation of alloreactive T cell proliferation
have an osteopetrotic phenotype (osteosclerosis and (Anderson et al., 1997; Wong et al., 1997).
RANK 1697
(cid:15) Regulation of chondrocyte development (Kong THERAPEUTIC UTILITY
et al., 1999a; Li et al., 2000).
(cid:15) Regulation of calcium metabolism (Li et al., 2000). Effect of treatment with soluble
(cid:15) Mediating the effects of calciotropic hormones and
receptor domain
proresorptive cytokines on bone metabolism (Li
et al., 2000).
sRANK-Ig fusion protein has similar biological
activity to OPG, although it is somewhat less potent
Phenotypes of receptor knockouts
(Hsu et al., 1999). Administration of sRANK-Ig into
and receptor overexpression mice mice blocks osteoclastogenesis and inhibits bone
resorption, and acts as an antiresorptive agent in
diseasemodelscharacterizedbypathologicalincreases
As one would predict from the effects of trans-
in osteoclast activity. See the chapter on OPG for a
genically delivered OPG, sRANK-Ig expressed in
description for its potential uses in the treatment of
transgenic mice blocks RANKL-induced osteoclasto-
human diseases.
genesis, leading to increases in bone mass similar to
native OPG (Hsu et al., 1999). sRANK-Ig transgenic
mice have severe osteopetrosis, characterized by a Effects of inhibitors (antibodies) to
defectinboneresorptionandlackmatureosteoclasts.
receptors
Normal osteoclast progenitors are present in these
mice, and osteoclastogenesis from these cells can be
demonstrated in vitro. There have been no reports of small molecules that
MicedeficientinRANKarealsoosteopetrotic,and inhibit RANK bioactivity. The analysis of RANK
lack osteoclasts (Dougall et al., 1999; Li et al., 2000), knockout mice provides insight into the effects that
a situationsimilar to that previously observedfor the inhibition of the RANK signaling pathway would be
RANKL(OPGL)(cid:255)/(cid:255)mice(Kongetal.,1999a).These likely to produce in vivo (see above). Polyclonal
results confirm that a major physiological role of antibodies to RANK have been isolated, and have
the OPG/RANKL/RANK axis is to regulate bone been shown to stimulate osteoclast development
metabolism and density. Like RANKL(cid:255)/(cid:255) mice, in vitro (Nakagawa et al., 1998; Hsu et al., 1999).
RANK(cid:255)/(cid:255) mice have a developmental defect in Yasuda et al. (1998) have prepared Fab fragments of
lymph node organogenesis that is not observed in this polyclonal antibody, and have shown that it
sRANK-Ig transgenic animals (Dougall et al., 1999; blocks receptor activation by RANKL during osteo-
Li et al., 2000). Interestingly, the defect in T cell clastogenesis in vitro.
development seen in RANKL(cid:255)/(cid:255) mice is not seen in
RANK(cid:255)/(cid:255)mice.Tcellshaverecentlybeenshownto
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