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From the Beth Israel Deaconess Medical Center,*
New
England Baptist Bone and Joint Institute, Harvard Institutes of
Medicine, Boston, Massachusetts; the Joslin Diabetes
Center
and the Orthopedic Biomechanics
Laboratory, Beth Israel Deaconess Medical
Center,
Harvard Medical School, Boston,
Massachusetts; the Institute for Biomedical
Engineering,
ETH and University of
Zürich, Zürich, Switzerland; and the Department of
Pathology and Lab Medicine,¶
University of
Pennsylvania School of Medicine, Philadelphia, Pennsylvania
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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B ligand (TRANCE/RANKL) is
an essential factor for osteoclast differentiation. In addition to its
role in osteoclast differentiation and activation, TRANCE/RANKL
also functions to augment T-cell dendritic cell cooperative
interactions. To further evaluate the role of osteoclasts in focal bone
erosion in arthritis, we generated inflammatory arthritis in
the TRANCE/RANKL knockout mouse using a serum transfer model that
bypasses the requirement for T-cell activation. These animals exhibit
an osteopetrotic phenotype characterized by the absence of osteoclasts.
Inflammation, measured by clinical signs of arthritis and
histopathological scoring, was comparable in wild-type and
TRANCE/RANKL knockout mice. Microcomputed tomography and
histopathological analysis demonstrated that the degree of bone erosion
in TRANCE/RANKL knockout mice was dramatically reduced compared to that
seen in control littermate mice. In contrast, cartilage erosion
was present in both control littermate and TRANCE/RANKL knockout mice.
These results confirm the central role of osteoclasts in the
pathogenesis of bone erosion in arthritis and demonstrate distinct
mechanisms of cartilage destruction and bone erosion in this animal
model of arthritis.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The presence of osteoclasts at sites of
focal bone erosion in RA and in animal models of arthritis suggests
that factors leading to osteoclast differentiation and activation may
play an important role in the pathogenesis of these erosions. An
essential factor for osteoclast differentiation, designated
osteoprotegerin (OPG) ligand,15
and osteoclast
differentiation factor,16
has recently been identified.
This protein was originally identified as a T-cell product, tumor
necrosis factor-related activation-induced cytokine (TRANCE), that can
regulate dendritic cell function and survival,17
and as
receptor activator of nuclear factor-B ligand
(RANKL).18
In this study we refer to this factor as
TRANCE/RANKL. In vitro studies using bone marrow co-culture
models have demonstrated that many of the factors that enhance
osteoclast formation or activity mediate their effects at least in part
by up-regulating the expression of TRANCE/RANKL on cells of the
osteoblast lineage.19-22
OPG,23
also known
as osteoclastogenesis inhibitory factor24
is a soluble
decoy receptor for TRANCE/RANKL. OPG binds TRANCE/RANKL with high
affinity and thus prevents the interaction of TRANCE/RANKL with its
cognate receptor, receptor activator of nuclear factor-B (RANK).
The essential role of TRANCE/RANKL in osteoclast differentiation is demonstrated by the phenotype of mice in which this gene has been deleted. TRANCE/RANKL knockout (KO) mice exhibit severe osteopetrosis and defective tooth eruption associated with a complete absence of osteoclasts,25 irregular bone surfaces because of the absence of remodeling, abnormal growth plates with club-shaped long bones, and growth retardation at several skeletal sites.26 In addition, these mice demonstrate defects in B-cell and T-cell maturation, as well as an absence of lymph nodes, supporting a role for this factor in immune cell differentiation.25,27 Furthermore, TRANCE/RANKL has been demonstrated to enhance the viability and adjuvant properties of dendritic cells resulting in the activation and proliferation of T-cells. Its expression is also up-regulated in T-cells after T-cell receptor stimulation.17,18,28
A role for TRANCE/RANKL in bone resorption in RA is suggested by the identification of TRANCE/RANKL mRNA3,29 and protein29 in cultured synovial fibroblasts from patients with RA and in CD4+ and CD8+ T lymphocytes in RA synovial tissues.3,30,31 Additional evidence that TRANCE/RANKL plays a critical role in the pathogenesis of bone erosion in inflammatory arthritis comes from studies in the rat adjuvant arthritis model, a T-cell-driven experimental arthritis.30 Arthritic rats treated with OPG early in the course of arthritis demonstrated only minimal erosion of cortical and trabecular bone, as compared with severe bone erosion in untreated control animals. Treatment with OPG also prevented osteoclast accumulation, whereas destruction of bone in untreated arthritic animals was accompanied by the accumulation of large numbers of TRAP+ osteoclast-like cells.30 OPG treatment in an animal model of arthritis that is dependent on T-cell activation, however, has the potential for blocking not only the effects of TRANCE/RANKL on osteoclast differentiation and activation, but also the influence of TRANCE/RANKL on T-cell-dendritic cell interactions.
To more definitively determine the role of TRANCE/RANKL on bone erosion in arthritis independent of its role in inflammation, we induced arthritis in TRANCE/RANKL KO mice using a serum transfer model. This model is a variant of a well-described animal model in which T-cell transgenic K/BxN mice develop spontaneous autoimmune arthritis. This spontaneous arthritis is dependent on T-cell B-cell interactions resulting in the production of pathogenic anti-glucose-6-phosphate isomerase antibody.32-34 The arthritis displays many of the characteristic features of RA including leukocyte invasion in affected joints, pannus formation, and cartilage and bone destruction. Transfer of serum containing anti-glucose-6-phosphate isomerase antibody results in the development of arthritis in recipient mice.33 Serum transfer arthritis is rapid in onset and histologically resembles the spontaneous arthritis. However T-cells and B-cells are not required for this phase of the arthritis and, once produced, the anti-glucose-6-phosphate isomerase antibodies are sufficient to confer disease.33 The serum transfer model provides an opportunity to investigate the role of TRANCE/RANKL on osteoclastogenesis and bone erosion in an inflammatory arthritis that resembles RA but is independent of cooperative T cell-dendritic cell interactions.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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As previously described KRN T-cell transgenic mice maintained on the C57BL/6 background were crossed with nonobese diabetic mice to generate K/BxN mice that develop spontaneous arthritis.33,34 The generation of the TRANCE/RANKL-deficient mice has been described.26 The mice used in the present experiments were (C57BL/6 x 129)F2 background. Control mice (Ctl) were matched littermates (+/- or +/+ genotypes). As the TRANCE/RANKL KO mouse phenotype includes severe osteopetrosis with failure of tooth eruption, these mice were maintained with powdered food in the cage. These experiments were reviewed by the Harvard Medical School Institutional Animal Care and Use Committee (IACUC), protocol no. 3224, and the University of Pennsylvania IACUC, approval no. 702636.
Generation of Arthritis by K/BxN Serum Transfer
K/BxN serum pools were prepared from arthritic mice at 60 days of age. Arthritis was induced in recipient mice by intraperitoneal injection (10 to 12.5 µl serum/g weight) in 200 to 250 µl total volume at days 0 and 2, and monitored throughout the next 12 days. For follow-up of longer duration, mice were reinjected with 200 to 250 µl of serum (10 to 12.5 µl serum/g weight) on days 7 and 12 or 14. Five arthritic TRANCE/RANKL KO mice and their matched control littermates were analyzed in five different experiments. Animals were sacrificed 12 to 13 days (experiments A and B) and 21 days (experiments C, D, and E) after initial serum injection to assess both the acute and chronic phases of the arthritis.33 Phosphate-buffered saline (PBS)-injected controls were sacrificed 21 days after the initial injection (experiments C and D). A clinical index was determined throughout time -1 point for each affected limb; 0.5 for a limb with only mild swelling/redness or only a few digits affected. Ankle thickness was measured by a caliper,33 and ankle thickening was defined as the difference in ankle thickness vis-a-vis the day 0 measure. Numerical values derived from these measurements were MaxAT (maximum ankle thickness) and AUC(0-12)AT (the integral of ankle thickening throughout the initial 12 day observation period) (Ji et al, submitted). To monitor new bone formation, a feature of this model of arthritis, mice in experiment D were also injected intraperitoneally with 15 mg/kg body weight of tetracycline hydrochloride (Sigma, St. Louis, MO) 2 days before and 18 days after the initial serum injection.
Microcomputed Tomographic (MicroCT) Imaging and Histology
Inflamed hind limbs were assessed by microCT and histology. Hind limbs were collected and the knee and ankle joints were separated at the mid tibia. Specimens were fixed in 4% paraformaldehyde for a minimum of 12 hours. For microCT imaging, ankle and forefoot joints were analyzed by means of a compact fan-beam-type microCT system (µCT 20; Scanco Medical AG, Bassersdorf, Switzerland35 ). This system has been used in previous studies in which microCT images have been demonstrated to closely correlate with bone histomorphometric analysis in murine and human samples.36,37
Lower hind limbs were placed in formalin-filled air-tight cylindrical
containers marked with an axial alignment line to allow for consistent
positioning of the specimens. Analysis consisted of a scout view,
selection of the examination volume, automatic positioning,
measurement, off-line reconstruction, and evaluation. For each sample,
200 microCT slices 17-µm apart were acquired, covering the entire
medial-lateral width of the ankle. Images were reconstructed in
1024 x 1024 pixel matrices providing a nominal resolution of 17
µm. A constrained three-dimensional Gaussian filter was used for
partial suppression of the noise in the
volumes.38
All samples were filtered according to the
same parameters for filter width (1.0) and filter
support.1
Three-dimensional visualization was performed
according to a previously described method.39
All
two-dimensional slices from the three-dimensional stack of microCT
images were assessed for bone erosion by two independent observers
(D.S. and R.M.). A two-dimensional mid-sagittal slice comprising a
detailed view of tibia, talus, and forefoot bones was chosen for
careful correlation with histological sections.
For histological analysis specimens were dissected to remove skin and
outer muscle and demineralized for 2 weeks in 14%
ethylenediaminetetraacetic acid followed by paraffin embedding (Citadel
1000; Shandon, Pittsburgh, PA). For each specimen at least 40 5-µm
sagittal serial sections were cut. At least every fifth section was
stained with hematoxylin and eosin (H&E) (Sigma) for evaluation of
inflammation, bone erosion, and cartilage destruction. An adjacent
section was stained with toluidine blue (Sigma) for specific evaluation
of proteoglycan. TRAP staining was performed by a modification of a
previously described method.40
Briefly, sections were
incubated for 15 minutes at 37°C in freshly prepared 0.1 mol/L Tris
buffer, pH 5.0, 1.35 mmol/L naphthol AS-MX phosphate (Sigma), 0.362
mol/L N,N-dimethylformamide, 3.88 mmol/L Violet
LB salt (Sigma), and 25 mmol/L sodium tartrate. Slides were rinsed for
10 minutes and counterstained with hematoxylin. For assessment of new
bone formation, one hind paw from the tetracycline-injected group of
mice was fixed as for histology followed by dehydration in ascending
grades of ethanol and embedding in OsteoBed resin (methacrylate;
Polysciences, Warrington, PA) according to the manufacturer’s
instructions. One-µm sections were cut using a Sorvall Porterblum
MT-2B ultramicrotome with a glass knife. New bone formation was
visualized using fluorescent microscopy (Nikon, Tokyo, Japan).
Histopathological Scoring
Histopathological scoring was performed as previously
described41
with the following minor modifications. The
tibio-talar joint and forefoot joints were scored separately and the
scoring criteria were altered to allow for independent scoring of these
joint areas. Mild edema was included only in the minimal inflammation
score because it is an early feature of this animal model of
arthritis.34
Osteoclast quantification was removed from
the criteria for bone erosion because of the total absence of
osteoclasts in the TRANCE/RANKL KO mice.25,26
At least six
H&E-stained sections were scored by two independent observers (A.R.P.
and E.M.G.) at low power for inflammation, and low and high power for
bone erosion. Serial toluidine blue-stained sections were scored for
cartilage damage and proteoglycan loss in areas remote from inflamed
synovium (pannus), and cartilage damage in areas adjacent to pannus was
scored on H&E-stained sections as outlined in Table 1
. The mean score for each
histopathological feature was calculated.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The susceptibility of TRANCE/RANKL-deficient mice to K/BxN
arthritis was tested in a serum transfer protocol. Knockout mice and
control littermates (Ctl) were injected with serum from 60-day-old
K/BxN arthritic mice, and the progression of arthritis was followed
throughout the next 3 weeks. The onset of clinical signs of arthritis
and ankle thickening occurred between days 1 to 3 in both the KO and
Ctl mice (Figure 1A)
. The disease then
progressed in a similar manner in both types of mice, with a rate of
ankle thickening consistent with previous observations in inbred mouse
strains33,42
The only clinical difference observed
was a consistently but modestly lower plateau level of ankle thickening
beyond day 7 in the TRANCE/RANKL KO mice (Figure 1B)
. AUC(0-12)AT (the
integral of ankle thickening throughout the initial 12-day observation
period) and MaxAT (maximum ankle thickness) demonstrated a similar
severity and rapidity of disease development in TRANCE/RANKL KO and Ctl
mice (Figure 1C)
. Inflammation was specifically assessed using
histopathological scoring as outlined in Table 1
. Both the TRANCE/RANKL
KO and Ctl mice demonstrated moderate to marked inflammation (Figure 1D)
at the time of sacrifice. Taken together, these data indicate that
there is little difference in the degree of inflammation in
TRANCE/RANKL KO and Ctl with serum transfer arthritis. Neither the
PBS-injected Ctl or TRANCE/RANKL KO mice showed signs of inflammation
(Figure 1)
.
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MicroCT and histopathological analyses were used to assess the
degree of bone erosion in TRANCE/RANKL KO and Ctl mice with serum
transfer arthritis. Areas of bone erosion were apparent on microCT
images of all arthritic Ctl mice at both time points studied, and
appeared as ragged bone surfaces and gaps in the cortical and
trabecular bone (Figure 2A)
. The degree
of bone erosion in the arthritic Ctl mice was striking even in mice
sacrificed on day 12 (data not shown). Erosion of cortical and
trabecular bone evident on the microCT images correlated well with
focal and full thickness cortical and trabecular bone erosions present
in the matched H&E sections as demonstrated in a representative
arthritic Ctl mouse sacrificed on day 21 (Figure 2, A and B
,
asterisks).
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; C to
F).25,26
PBS-injected TRANCE/RANKL KO mice (Figure 2, E and F)
were used as controls for the assessment of bone erosion in
arthritic TRANCE/RANKL KO mice. Bone in the TRANCE/RANKL KO mice
is primarily woven bone because of the absence of bone
remodeling.26
Thin cortical bone is present but has an
irregular surface (Figure 2F)
and trabecular bone, although mineralized
(as detected by microCT analysis; Figure 2, C and E
), has a high
proteoglycan content, demonstrated by toluidine blue staining. In
contrast to the findings in arthritic Ctl mice, microCT images of
TRANCE/RANKL KO mice with arthritis demonstrated continuous bone
surfaces and showed evidence of dramatic reduction in bone erosion at
both time points studied (Figure 2C)
. Histological analysis was
performed on matched H&E sections to correlate with the microCT
observations (Figure 2, C and D)
. H&E sections confirmed that cortical
bone surfaces were predominantly intact (Figure 2D)
indicating that the
TRANCE/RANKL KO mice are protected from bone erosion in this model of
arthritis. TRAP histochemistry was performed to determine whether TRAP+
multinucleated cells were present at sites of bone erosion in this
model. Numerous TRAP+ multinucleated cells were present on bone at
sites of cortical and trabecular bone erosion in arthritic Ctl mice
(Figure 3
; A, B, and E). In contrast,
TRAP staining confirmed the complete absence of TRAP+ multinucleated
cells in TRANCE/RANKL KO mice (Figure 3, C and D)
.
|
. Bone erosion was more prominent in the forefoot in
arthritic Ctl mice. Therefore, forefoot and tibio-talar joints were
scored separately to more accurately reflect the disease process.
Figure 4A
demonstrates bone erosion
scores for paired Ctl and TRANCE/RANKL KO mice with arthritis (and
PBS-injected controls in some experiments) and confirms that bone
erosion is dramatically reduced in TRANCE/RANKL KO mice with serum
transfer arthritis. Careful histological analysis of ankle and forefoot
joints was performed in arthritic TRANCE/RANKL KO mice and comparisons
were made to PBS-injected TRANCE/RANKL KO mice. The abnormal
osteopetrotic bone phenotype in the TRANCE/RANKL KO mice with irregular
bone shapes and prominent nutrient artery entry points made definitive
exclusion of bone erosion impossible (Figure 3F and G)
. Any irregular
bone feature in an area of synovitis that could not be definitively
identified as a manifestation of the osteopetrotic bone phenotype was
scored as erosion. The degree of focal bone erosion that was present in
the TRANCE/RANKL KO mice with arthritis was small.
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; A to D, arrows), and the volar surface of the
calcaneus (not shown). These bone deposits were confirmed as sites of
new bone formation by tetracycline labeling (data not shown). The new
bone was remodeled by TRAP+ multinucleated cells in Ctl but not in
TRANCE/RANKL KO mice. This is reflected by the higher density of areas
of bone deposition in the TRANCE/RANKL KO mice demonstrated on microCT
(Figure 2C)
. Cartilage Destruction Occurs in TRANCE/RANKL KO Mice
Cartilage destruction was assessed in the tibio-talar joint and in
joints within the forefoot in Ctl and TRANCE/RANKL KO mice by scoring
of sections stained with toluidine blue, which stains cartilage
proteoglycan, and by examination of loss of cartilage in direct contact
with pannus tissue on H&E-stained sections. Toluidine blue-stained
sections revealed loss of cartilage proteoglycan in arthritic Ctl and
TRANCE/RANKL KO mice as compared to PBS-injected control mice (Figure 5
; A to C). Scoring of toluidine
blue-stained sections revealed loss of articular cartilage in all mice
with arthritis. The degree of proteoglycan and chondrocyte loss showed
a trend toward higher scores in the arthritic Ctl mice (Figure 4B)
.
However in these mice, complete loss of articular cartilage was noted
in areas of subchondral bone erosion where the scaffolding subchondral
bony plate deep to articular cartilage was completely lost (Figure 5D)
.
Similar areas of subchondral bone erosion and associated loss of
articular cartilage were absent in KO mice (Figure 5E)
. Cartilage loss
in areas of articular cartilage adjacent to inflamed synovium was
present in both Ctl and TRANCE/RANKL KO mice (Figure 5F)
, with a
similar trend toward higher scores in Ctl mice (data not shown). The
results indicate that cartilage damage occurs in both the TRANCE/RANKL
KO and Ctl mice with serum transfer arthritis although the degree of
damage seems to be milder in the TRANCE/RANKL KO mice.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We demonstrate in this murine model that on transfer of arthritogenic serum, TRANCE/RANKL KO mice develop inflammation similar to that seen in the Ctl mice. On the other hand, bone erosion in the absence of TRANCE/RANKL is dramatically reduced compared to Ctl mice. Large numbers of multinucleated TRAP-positive cells are present in resorption lacunae in areas of bone erosion in arthritic Ctl mice, and are completely absent in the arthritic TRANCE/RANKL KO mice, demonstrating the absolute requirement for this factor in osteoclastogenesis in this model of inflammatory arthritis. Small foci of bone irregularity adjacent to areas of synovitis were present in the arthritic TRANCE/RANKL KO mice that could not be definitively identified as a manifestation of the osteopetrotic bone phenotype. These were scored as erosions. These mice do have synovial fibroblasts, activated macrophages, and other cell types that have been implicated as playing a primary role in bone erosion. However, culture of monocyte/macrophage lineage cells on dentine slices reveals that they possess minimal capacity to directly resorb mineralized bone.43,44 Similar studies with synovial fibroblasts have not yet been reported. Our observations provide additional evidence that the contribution of these and other cell types to focal bone erosion is limited in the absence of osteoclasts.
This study and the previously reported OPG treatment of mice with adjuvant arthritis30 demonstrate the critical role of osteoclasts in the pathogenesis of focal bone erosion. In both studies, however, osteoclasts are essentially absent from the time of arthritis onset. In this study, TRANCE/RANKL is absent leading to a complete inability to generate osteoclasts, and in the latter study, OPG treatment was initiated at the onset of arthritis, blocking osteoclastogenesis. These studies do not directly address the possibility that other cell types could contribute to bone erosion in concert with osteoclasts. It has been suggested that activated macrophages, synovial fibroblasts, and other cell types capable of producing matrix-degrading proteases contribute to bone erosion.4,45-47 For example, synovial fibroblasts and monocyte/macrophages have been shown to produce mRNA for cathepsin K,4,44 a cysteine protease active in the degradation of the organic matrix of bone. Studies addressing the possible cooperative interactions of osteoclasts and other cell types in bone erosion in arthritis will be of great interest.
An important observation from studies in this arthritis model is that the differentiation and activation of osteoclasts can occur in the arthritic context in the absence of T-cell input. Kong and colleagues30 proposed that in the adjuvant arthritis model TRANCE/RANKL produced by activated T-cells in the arthritic lesion was responsible for osteoclast activation and focal bone destruction. In serum transfer arthritis expression of TRANCE/RANKL by activated T-cells does not seem to be required for the generation of focal bone erosion because RAG knockout mice that lack mature lymphocytes develop bone erosions (data not shown).33 Recent results show that the synovitis in the K/BxN model is dependent on complement and Ig-FcR receptors (Ji et al, submitted). Once generated, osteoclasts may be activated by signals mediated through these pathways or, perhaps more likely, respond to indirect signals from activated synoviocytes or other cell types. Synovial fibroblasts and cells of the osteoblast lineage have been demonstrated to express TRANCE/RANKL,3,19,29 and TRANCE/RANKL may be the molecular mediator of this interaction. It will be of great importance to further elucidate these mechanisms.
In contrast to the findings in bone, definite cartilage destruction is present in both Ctl and TRANCE/RANKL KO mice with serum transfer arthritis, demonstrating that the mechanisms of cartilage destruction are distinct from those of bone erosion and that TRANCE/RANKL is not required for cartilage destruction in this model. Cartilage damage was assessed by analysis of areas of direct pannus invasion into cartilage and by evaluation of cartilage matrix degradation by toluidine blue staining in sites remote from pannus. Scoring of cartilage loss in both cases demonstrated a trend toward milder cartilage damage in the TRANCE/RANKL KO mice. This effect was due at least in part to the presence of large subchondral bone erosions with complete loss of subchondral bone and associated dissolution of cartilage in arthritic control mice. Subchondral bone erosions with associated cartilage loss were absent in the TRANCE/RANKL KO mice. These results differ from results previously reported in mice with adjuvant arthritis treated with OPG. In that model, significant protection of cartilage matrix was noted in OPG-treated mice, although modest focal cartilage damage was seen in areas of cartilage in direct contact with pannus. As suggested by Kong and colleagues,30 the cartilage protection demonstrated in their study may also be due, in part, to the protection of scaffolding subchondral bone because subchondral bone erosion is a prominent feature of the adjuvant arthritis model. The differences in cartilage protection in these two studies may also reflect differences in the degree of primary cartilage damage intrinsic to these arthritis models.41 Although TRANCE/RANKL may play a modulatory role in cartilage damage our results do not support a requirement for TRANCE/RANKL in cartilage destruction in this serum transfer model of arthritis independent of its effects on associated bone erosion.
An interesting feature of the serum transfer model of arthritis is new bone formation.33 In this model the deposition of new woven bone occurred on cortical surfaces at reproducible anatomical locations including the anterior tibia, the volar surface of the calcaneus, and the dorsal surfaces of forefoot bones. The only notable difference in new bone formation between the arthritic TRANCE/RANKL KO and arthritic Ctl mice was the presence of TRAP+ multinucleated osteoclast-like cells in areas of new bone formation in Ctl mice, suggesting ongoing remodeling of new bone in these mice. These observations demonstrate that in this model of arthritis, TRANCE/RANKL is not required for the formation of new bone.
These studies highlight osteoclasts as important targets for therapeutic intervention to block focal bone erosion in inflammatory arthritis. Data from other animal models of inflammatory arthritis showing that bisphophonates prevent focal bone resorption lend support to this hypothesis.48 However, in patients with RA, treatment with anti-resorptive therapies alone, including bisphosphonates or calcitonin, have not prevented the progression of focal bone erosions.49,50 This could be because of inadequate dosing of these drugs. Alternatively, in the case of bisphosphonates, lack of efficacy may be because of a limited ability to concentrate the drug at sites of inflammation. The results reported here support the hypothesis that therapies interfering with osteoclast differentiation or activity, including agents that block TRANCE/RANKL, may prove useful in the treatment of RA.
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Acknowledgements |
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Footnotes |
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Supported by the Arthritis Foundation of Australia and the National Health and Medical Research Council (to A. R. P.), an M. E. Müller Professorship in Bioengineering (to R. M.), and the National Institutes of Health (grant RO1-DK46773 to S. R. G.).
A. R. P. and H. J. contributed equally to this work.
Accepted for publication July 23, 2001.
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