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Inflammation is preceded by tumor necrosis factor-dependent infiltration of mesenchymal cells in experimental arthritis.

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ARTHRITIS & RHEUMATISM
Vol. 46, No. 2, February 2002, pp 507–513
DOI 10.1002/art.10126
© 2002, American College of Rheumatology
Published by Wiley-Liss, Inc.
Inflammation Is Preceded by
Tumor Necrosis Factor–Dependent Infiltration of
Mesenchymal Cells in Experimental Arthritis
L. Marinova-Mutafchieva,1 R. O. Williams,1 K. Funa,2 R. N. Maini,1 and N. J. Zvaifler3
Objective. To determine the involvement of mesenchymal progenitor cells in the induction of collageninduced arthritis (CIA).
Methods. DBA/1 mice were immunized with type
II collagen in adjuvant or adjuvant alone, and the
presence of mesenchymal cells in the joints of prearthritic mice was studied by immunohistochemistry.
Results. An analysis of the joints on day 10
postimmunization (at least 10 days before the onset of
arthritis) revealed synovial hyperplasia without leukocytic infiltration. Large, round cells expressing bone
morphogenetic protein receptors (BMPRs), which serve
as markers for primitive mesenchymal cells, were
present in increased numbers in the bone marrow
adjacent to the joint, in the synovium itself, and within
enlarged bone canals that connect the bone marrow to
the synovium. Similar changes were observed in mice
given adjuvant without collagen. Adjuvant-induced infiltration of BMPRⴙ cells and enlargement of bone
canals were abrogated by anti–tumor necrosis factor
(anti-TNF) treatment and were absent in TNFR p55/
p75ⴚ/ⴚ mice. Increased numbers of bone marrow cells
and enlarged bone canals were observed in nonimmunized TNF transgenic mice (which spontaneously develop arthritis).
Conclusion. These findings suggest that in CIA,
Britain.
there is an antigen-independent (innate) prearthritic
phase that prepares the joint for the subsequent
immune-mediated arthritis. The induction phase involves marrow-derived mesenchymal cells and requires
the presence of TNF.
Rheumatoid arthritis (RA) is characterized by
chronic inflammation of the synovial tissues and destruction of bone and cartilage, resulting in loss of joint
function. Although much of the pathology of RA can be
attributed to cells of the immune system, it is also
possible that nonhematopoietic cells play a role in the
initiation and/or perpetuation of the disease. For example, we have previously documented the presence of
mesenchymal progenitor cells (MPCs) bearing receptors
for bone morphogenetic proteins (BMPs) in the synovial
membrane and synovial fluid of RA patients (1), although the pathophysiologic relevance of these cells is
unclear. MPCs operate under the influence of BMPs, a
group of 20 dimeric proteins belonging to the transforming growth factor ␤ superfamily (2,3). BMPs direct the
differentiation of MPCs into osteoblasts, chondrocytes,
and adipocytes and are endogenous regulators of skeletal development (3–5).
BMPs exert their diverse biologic effects through
membrane receptors of 2 types, BMP receptor I (BMPRI) and BMPRII, on MPCs. BMPRI is further subclassified into BMPRIA and BMPRIB. The formation
of heterodimeric complexes of BMPRI and BMPRII
induces signal transduction following ligand binding
(6,7). Antibodies to BMPRs allow the identification of
MPCs in situ. For example, during organogenesis of
mouse embryos, cells expressing BMPRIA and
BMPRIB can be demonstrated in areas of mesenchymal
precartilage condensation and in premuscle or on cells
in areas of developing cartilage and bone. In previous
studies we have used anti-BMPR antibodies to characterize a population of MPCs in the blood of healthy
Supported by the Arthritis Research Campaign of Great
1
L. Marinova-Mutafchieva, MD, PhD, R. O. Williams, PhD,
R. N. Maini, MB, FRCP: Kennedy Institute of Rheumatology Division, Imperial College School of Medicine, London, UK; 2K. Funa,
MD, PhD: Gothenburg University, Gothenburg, Sweden; 3N. J.
Zvaifler, MD: University of California, San Diego.
Address correspondence and reprint requests to R. N. Maini,
MB, FRCP, Kennedy Institute of Rheumatology Division, Imperial
College School of Science, Technology and Medicine, The Charing
Cross Hospital Campus, Arthritis Research Campaign Building, 1
Aspenlea Road, London W6 8LH, UK; E-mail: r.maini@ic.ac.uk.
Submitted for publication May 22, 2001; accepted in revised
form September 24, 2001.
507
508
MARINOVA-MUTAFCHIEVA ET AL
individuals (8) and in the synovial tissue of patients with
RA (1).
The presence of MPCs in the joints of patients
with RA raises an important question. Do MPCs appear
in the joint as a result of the inflammatory process or do
they arrive before the onset of inflammatory changes? In
this study, we used the murine collagen-induced arthritis
(CIA) model to address this question and, in addition, to
identify which factor(s) may be involved in recruiting
MPCs to the joint. Our findings reveal that BMPR⫹
MPCs accumulate in the bone marrow and synovial
tissue of mice prior to the onset of CIA and that their
presence in prearthritic joints is regulated by tumor
necrosis factor (TNF) and is associated with the opening
of vascularized bone canals that link the bone marrow to
the synovium.
MATERIALS AND METHODS
Mice. Male DBA/1 mice (8–12 weeks of age) were
used for induction of CIA. Female TNF transgenic mice (6–8
weeks of age) with an original background of C57BL6 ⫻ CBA
(obtained from Dr. George Kollias, Hellenic Pasteur Institute,
Athens, Greece) were backcrossed with DBA/1 mice (19
generations). Male TNFR p55/p75⫺/⫺ (TNFR⫺/⫺) mice (6–8
weeks of age) were obtained from Dr. Jacques Peschon
(Immunex, Seattle, WA) and were from a C57BL6 ⫻ 129
background.
Immunization. DBA/1 mice were immunized intradermally at the base of the tail with 200 ␮g of bovine type II
collagen (CII) emulsified in Freund’s complete adjuvant
(CFA; Difco, West Molesley, UK). Alternatively, mice were
immunized with CFA emulsified with an equal volume of
phosphate buffered saline (PBS). Mice were inspected daily
for signs of arthritis (erythema and/or joint swelling). They
were killed 10–13 weeks postimmunization, and hind paws
were removed above the ankle joint and processed for routine
histologic and immunohistochemistry study.
Antibodies. Anti-TNF monoclonal antibody (mAb)
TN3-19.12 (9) was a gift from Robert Schreiber (Washington
University Medical School, St. Louis, MO), in conjunction with
Celltech (Slough, UK). Anti-BMPR antibodies consisted of
polyclonal rabbit antisera (obtained from Dr. C.-H. Heldin,
Ludwig Institute for Cancer Research, Uppsala, Sweden) and
were prepared against synthetic peptides corresponding to the
intracellular juxtamembrane parts of the type IA, type IB, and
type II receptors of BMP (10,11). The antisera were affinity
purified and tested for specificity by immunoprecipitation of
crosslinked complexes of cultured cells transfected with the
appropriate BMPR complementary DNA.
Immunohistochemistry studies. Immunolocalization
of BMPR was carried out as previously described (1). Briefly,
hind paws were embedded in OCT embedding matrix (Cell
Path, Hemel Hemstead, UK) and then snap frozen. Sagittal
sections (8 ␮m) were cut using a cryostat and a tungsten
carbide knife, and transparent adhesive tape was used to attach
the sections to the slide. Sections were fixed in ice-cold 4%
phosphate buffered paraformaldehyde (pH 7.4) for 20 minutes
and then washed in PBS. All further incubations and washes
were carried out using PBS. After endogenous peroxidase
activity was blocked with 0.1M sodium azide containing 1%
H2O2, the specimens were incubated with 10% normal goat
serum, 2% normal rat serum, and 1% bovine serum albumin
(BSA) for 30 minutes at room temperature to eliminate
nonspecific binding.
Specimens were then incubated with primary antibodies (1.2 ␮g/ml of anti-BMPRIA, 1.0 ␮g/ml of antiBMPRIB, or 1.5 ␮g/ml of anti-BMPRII), followed by biotinylated secondary antibody (Vector, Burlingame, CA). The
antibody–biotin conjugates were detected with an avidin–
biotin–peroxidase complex (Vectastain Elite ABC; Vector).
Color reaction was developed using 3-amino-9-ethyl-carbazole
(Merck, Luttenworth, UK), and finally the specimens were
lightly counterstained with Mayer’s hematoxylin. Controls consisted of normal rabbit IgG (Vector), 1% BSA in PBS, or
antibodies preabsorbed with the respective peptide used for
immunization.
A staining procedure similar to that described
above was used to identify cell surface molecules. To detect
CD34⫹ cells, sections were stained with rat anti-mouse CD34
(PharMingen, San Diego, CA). Macrophages were detected
with rat anti-mouse F4/80 (Serotec, Oxford, UK). CD4⫹ or
CD8⫹ cells were detected with the appropriate rat anti-mouse
antibody (PharMingen).
Microscopic analysis. Sections were examined using
an Olympus BH2 microscope and characterized with a computer image analyzer (AnalySIS; Soft Imaging System GmbH,
Munster, Germany), under blinded conditions. The entire
tissue section of a whole paw was examined to localize and
identify areas with positively stained cells. Synovial tissue was
obtained from the metatarsophalangeal (MTP) joint and
epiphyseal bone marrow regions of the same joint, and quantitative analysis was performed by color cell separation. For
each high-power field, data were expressed as region of
interest, i.e., the percent of the total area that exhibited
positive staining. To ensure that approximately the same areas
of tissue were studied for all of the BMP receptors, the staining
was carried out in adjacent serial sections. Adjacent sections
were also examined for the expression of CD4, CD8, F4/80, or
CD34 antigens. In addition to immunohistochemical staining,
sections from all hind limbs were stained with hematoxylin and
eosin or Safranin O in order to assess histopathologic changes
associated with the development of arthritis. The diameter of
bone canals in the “bare zone” (an area between the articular
margin and the junction of the capsule and periosteum) was
measured using the image analyzer.
Statistical analysis. Histologic and immunohistologic
data obtained by image analysis were subjected to analysis of
variance followed by Tukey’s test, to determine the significance
of differences between groups.
RESULTS
Histopathologic changes prior to onset of CIA.
Histologic analysis of joints removed 10 days after the
mice were immunized with CII in CFA (n ⫽ 15 mice)
TNF-DEPENDENT MESENCHYMAL CELL INFILTRATION IN ARTHRITIS
Figure 1. Presence of bone canals prior to onset of collagen-induced
arthritis. Shown is a sagittal section of proximal interphalangeal joint
from a mouse with synovial hyperplasia and an enlarged bone canal,
connecting the synovium (S) to the bone marrow (BM) at the bare
zone. The specimen was obtained 10 days after immunization with
collagen in adjuvant, before there was any clinical evidence of arthritis.
B ⫽ bone; C ⫽ cartilage (hematoxylin and eosin stained; original
magnification ⫻ 40).
revealed that the synovial tissues in 67% of proximal
interphalangeal (PIP) and 61% of MTP joints had
evidence of fibrin deposition and synovial hyperplasia.
The changes were localized to the bare zone (Figure 1).
No abnormalities were observed in distal interphalan-
509
geal (DIP) joints at this time. A 212% increase in the
number of bone marrow cells was seen in the epiphyseal
region of joints with synovial hyperplasia, compared with
the same area in normal joints without synovial hyperplasia.
Normal mouse joints have minute (⬃25 ␮m in
diameter) canals in the bare zone connecting the bone
marrow to the synovium. In joints with synovial hyperplasia, there was a significant increase in the size of these
canals compared with that in joints without hyperplasia
(P ⬍ 0.01). In addition, the bone canals in joints with
synovial hyperplasia appeared more vascularized than
those in nonimmunized joints and were found to contain
large, round cells with a morphology similar to that of
cells in the bone marrow (Figure 2). No leukocytic
infiltrates and no CD4⫹ or CD8⫹ lymphocytes were
observed in either normal or hyperplastic synovium 10
days after immunization.
Histopathologic changes in the joints of mice
immunized with CFA alone. To distinguish the separate
contributions of antigen (CII) and adjuvant (CFA) in
the induction of synovial hyperplasia, mouse joints were
analyzed histologically 12 days after the administration
of CFA alone. Approximately 38% of PIP and 52% of
MTP joints exhibited synovial hyperplasia and fibrin
deposition. Hyperplastic changes were not present in the
synovium of DIP joints. The epiphyseal areas of hyperplastic PIP and MTP joints showed an accumulation of
bone marrow cells. Moreover, joints that showed syno-
Figure 2. Presence of bone marrow cells in bone canals. A, An enlarged bone canal in the bare zone of a proximal interphalangeal (PIP) joint prior
to the onset of collagen-induced arthritis. In the canal are blood vessels (BV) containing large, round cells. B, A normal bone canal in an unaffected
PIP joint. Arrows indicate the margins of the canals at the junction with the synovium (S). B ⫽ bone; BM ⫽ bone marrow. (Hematoxylin and eosin
stained; original magnification ⫻ 200.)
510
Figure 3. Bone morphogenetic protein receptor–positive (BMPR⫹)
cells in collagen-induced arthritis. BMPRIA⫹ cells are evident in the
synovial tissue (S), bone marrow (BM), and the enlarged canals in the
bare zone and periosteal area 10 days after immunization with collagen
in adjuvant, prior to the onset of arthritis. Arrows indicate the location
of bone canals. B ⫽ bone; C ⫽ cartilage; JS ⫽ joint space (hematoxylin
and eosin stained; original magnification ⫻ 100).
vial hyperplasia also had larger canals in the bare zone,
similar to those seen in the joints of mice immunized
with CFA plus collagen. In joints with synovial hyperplasia, the canals were 2.5 times larger than in normal
joints (P ⬍ 0.01). Thus, canal enlargement (⬎35–40 ␮m)
was equivalent in mice that had been immunized with
collagen in adjuvant and those immunized with adjuvant
alone, and in both cases the canals were seen to contain
marrow elements.
Effect of immunization on accumulation of
BMPRⴙ cells. In sections from nonimmunized mice,
weak expression of BMPRIA and BMPRII on periosteal
cells and osteoblasts of cortical bone was occasionally
detected by immunohistochemistry, but no BMPR⫹
cells were observed in the synovial membrane. Some
chondrocytes in the articular cartilage situated close to
the epiphyses showed moderate staining for BMPRIA,
BMPRIB, and BMPRII. However, strong staining for
BMPRIA and BMPRII was observed exclusively on
large, round cells in the bone marrow. Ten days after
immunization with either CFA alone or CFA plus
collagen, the mice that developed synovial hyperplasia
had increased BMPRIA and BMPRII expression on
cells of the periosteum and on osteoblasts of cortical
bone. At the same time, large, round bone marrow cells
staining strongly for BMPRIA and BMPRII were found
to be accumulated in the epiphyseal region. Cells with
the same morphology were also seen in the enlarged
MARINOVA-MUTAFCHIEVA ET AL
canals in the bare zone and in hyperplastic synovium
(Figure 3). BMPRIA⫹ and BMPRII⫹ cells in the hyperplastic synovium were localized primarily in the subintima, although a proportion were found in the synovial
lining.
Role of TNF in accumulation of BMPRⴙ cells,
enlargement of bone canals, and synovial hyperplasia.
Previously, we and others have shown that TNF blockade during the induction phase of CIA delays the onset
of arthritis and reduces its subsequent clinical severity
(12–14). To evaluate the possible role played by TNF in
the subclinical changes observed in this study, mice were
immunized on day 0 with CFA alone, then injected
intraperitoneally with 300 ␮g of anti-TNF mAb (TN319.12) or PBS (6 animals in each group) on days 7, 9, and
11. On day 13 the animals were killed and their hind
paws analyzed. Anti-TNF treatment caused reductions
in the proportion of joints with hyperplasia and in the
size of bone canals (Figure 4). This treatment also led to
reductions in the numbers of BMPRIA⫹ and BMPRII⫹
cells in the bone marrow and synovium (Figure 5).
To further establish the importance of TNF in
the subclinical changes, TNFR⫺/⫺ mice (n ⫽ 12) were
immunized with CFA alone. On day 12, neither the
degree of synovitis nor the size of the canals differed in
CFA-immunized TNFR⫺/⫺ mice compared with nonim-
Figure 4. Inhibition of bone canal enlargement by tumor necrosis
factor (TNF) blockade. Freund’s complete adjuvant (CFA)–
immunized mice were treated on days 7, 9, and 11 with anti-TNF
monoclonal antibody or phosphate buffered saline (n ⫽ 6 per group).
On day 13, the mice were killed and the diameter of the canals was
determined by image analysis. Open bars ⫽ bone canals in proximal
interphalangeal joints; solid bars ⫽ bone canals in metatarsophalangeal joints. Values are the mean and SEM.
TNF-DEPENDENT MESENCHYMAL CELL INFILTRATION IN ARTHRITIS
Figure 5. Inhibition of accumulation of bone morphogenetic protein
receptor–positive (BMPR⫹) cells by tumor necrosis factor (TNF)
blockade. Freund’s complete adjuvant (CFA)–immunized mice were
treated on days 7, 9, and 11 with anti-TNF monoclonal antibody or
phosphate buffered saline (n ⫽ 6 per group). On day 13, the mice were
killed and BMPR expression in the bone marrow (A) and in the
synovium (B) was analyzed by immunochemistry, using antibodies
specific for BMPRIA (open bars), BMPRIB (not shown), and BMPRII (solid bars). Sections were studied by image analysis and the data
are expressed as the percent of the total area showing positive staining
(mean and SEM).
munized animals, and there was no evidence of bone
marrow cell accumulation in the epiphyseal areas. Furthermore, the expression of BMPRIA and BMPRII
on bone marrow cells at the epiphysis in TNFR⫺/⫺
511
mice immunized with CFA was similar to that in control, nonimmunized mice. Strikingly, no BMPRIA⫹ or
BMPRII⫺ cells were identified in the synovium of
CFA-immunized TNFR⫺/⫺ mice.
Finally, to confirm the role of TNF in promoting
marrow cellularity and enlargement of canals, joints
from nonimmunized human TNF (HuTNF) transgenic
mice, which spontaneously develop arthritis at ⬃3 weeks
of age, were examined. Interphalangeal joints from
6–8-week-old HuTNF transgenic mice exhibited a dramatic increase in the numbers of bone marrow cells at
the epiphysis compared with nontransgenic littermates
and even compared with DBA/1 mice immunized with
collagen in CFA or with CFA alone. For example, there
was a 5–8-fold increase in the numbers of bone marrow
cells at the epiphysis in HuTHF transgenic mice compared with mice given CFA alone or CFA plus collagen
(data not shown). Similarly, the size of the bone canals
was almost double the size of the canals in the hyperplastic joints of mice given collagen in CFA or CFA
alone (data not shown).
Origin of BMPRⴙ cells in the bone marrow and
synovium. Sequential sections of synovium and bone
marrow from nonimmunized mice or from mice immunized with collagen in CFA were examined immunohistologically (on day 10 after immunization) for coexpression of BMPRIA/BMPRII and CD34, a marker for
hematopoietic progenitor cells. In the bone marrow,
CD34⫹ cells and BMPRIA⫹ cells or BMPRII⫹ cells
were in proximity to each other, but no overlapping
staining was observed. In the synovium, CD34 expression was seen only on vascular endothelial cells in the
marginal bare zone, while BMPRIA and BMPRII expression was limited to cells with a large, round or
fibroblast-like morphology. Therefore, it appears that
BMPR⫹ cells arise from mesenchymal, rather than
hematopoietic, progenitor cells.
DISCUSSION
The results of this study show that the initiation
of synovial hyperplasia in CIA is accompanied by 2 early
events: 1) the enlargement of vascularized bone canals
that link the bone marrow and the synovium and 2) the
accumulation of BMPR⫹ cells in the synovial membrane
and bone marrow, in advance of inflammatory cell
accumulation and clinical onset of arthritis. These same
changes were observed in mice given CFA alone; therefore, we may assume that bone canal enlargement and
accumulation of BMPR⫹ cells are not dependent on
CII-specific immune responses. Moreover, the findings
512
that these changes are inhibited by anti-TNF treatment,
are absent in TNFR⫺/⫺ mice, and occur spontaneously
in TNF transgenic mice confirm the important role
played by TNF in these preinflammatory events. This
may explain the previous observation, by 3 independent
groups (12,13,15), that TNF blockade during the induction phase of CIA (prior to disease onset) reduces the
subsequent severity of disease.
The simultaneous presence of BMPR⫹ mesenchymal cells in the bone marrow and in the hyperplastic
synovium suggests a connection between these 2 juxtaposed tissues. Conventionally, the cellular elements that
accumulate in inflamed joint tissues are thought to come
from the circulation. Alternative routes are seldom
considered, although blood vessels and mesenchymal
elements that arise in the perichondrium and extend into
the epiphysis during the late stages of embryogenesis of
the appendicular skeleton in the mouse have been well
described (16,17).
The notion of a bone marrow–synovial connection is not new. Nakagawa et al proposed a role for bone
marrow cells in the pathogenesis of RA and tested the
idea in a CIA model (18). Stromal cells from the bone
marrow of rats were isolated by plastic adherence in
tissue culture, labeled, and then injected intraperitoneally into syngeneic rats 2 days before immunization with
collagen. At week 1, labeled cells were observed only in
the marrow, but at 2 weeks, labeled cells were found
“proliferating in the bone marrow and migrating into the
joint cavity through the canals at the bare zone.” In this
study, we have similarly demonstrated the presence of
BMPR⫹ mesenchymal cells in enlarged canals in the
bare zone and in the hyperplastic synovium.
Bone canal enlargement is not simply the result
of vasodilatation, as can be seen from our measurements
(Figure 4), but how can enlargement develop so quickly?
Using dual x-ray absorptiometry, Takagi et al demonstrated a significant local decrease in bone mineral
density in the knee joints of rats 7 days after CFA
injection, but 1 week before arthritis was clinically
apparent (19). More important, this was not a generalized response to adjuvant, because only the distal femur
and proximal tibia showed changes in bone mineral
density at this early stage. Those authors hypothesized
that the differences could be explained by the fact that
periarticular bone is primarily trabecular bone, and the
magnitude and rate of trabecular bone loss are greater
and faster than those of cortical bone loss (19).
The actual mechanism remains unexplained, but
the well-documented role of TNF in osteoporosis (20)
and in bone resorption in periodontal disease (21)
MARINOVA-MUTAFCHIEVA ET AL
indicates that TNF has an important function in bone
remodeling. Furthermore, the observed effects of TNF
blockade and the changes in TNF transgenic mice
constitute strong evidence that this cytokine is a major
participant in prearthritic epiphyseal bone remodeling
and expansion of bone canals. One further observation
that may explain the mechanism of opening up of bone
canals was the presence of activated osteoclasts in close
proximity to the enlarged canals (results not shown)
suggesting that it is an osteoclast-mediated process.
Histologic evidence of synovial hyperplasia antedating clinical arthritis was described in an early report
on light and electron microscopy findings in the knee
joints of Wistar and Sprague-Dawley rats immunized
with collagen (22). The investigators proposed 2 stages
in the development of CIA: an initial stage starting
around day 12 consists of fibrin deposition and synovial
hyperplasia in the joints, whether the animals develop
arthritis or not; later, a second stage occurs in a minority
of animals, in which there is a severe inflammatory
synovial reaction with bone and cartilage destruction.
Mesenchymal cells bearing BMPRs are the only new
cells in the hyperplastic prearthritic synovium. Their
significance remains to be defined, but since similar cells
in bone marrow and in rheumatoid synovial tissue
constitutively produce stromal cell–derived factor (1), a
potent chemokine for B cells, T lymphocytes, and monocytes (23), the role of primitive mesenchymal cells in the
induction phase of CIA may be to promote the accumulation of immunocompetent cells into the joint and
hence initiate the inflammatory phase.
In summary, we have shown that BMPR⫹ mesenchymal cells are among the earliest cells to arrive at
the prearthritic joint in CIA and are strongly associated
with early hyperplastic changes in the synovium. Although this study focused on early events in CIA, we
have previously shown that BMPR⫹ mesenchymal cells
are also present in patients with established RA (1),
suggesting that they are involved not only in early
synovial hyperplasia, but also in the chronic phase of
arthritis. Finally, these findings further elaborate the
complex role played by TNF in inflammatory arthritis.
ACKNOWLEDGMENTS
The authors are indebted to Robert Shreiber and
Celltech for providing TN3-19.12, to George Kollias for providing HuTNF transgenic mice, and to Jacques Peschon for
providing TNFR⫺/⫺ mice.
TNF-DEPENDENT MESENCHYMAL CELL INFILTRATION IN ARTHRITIS
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necrosis, factors, experimentov, inflammation, mesenchymal, arthritis, infiltrating, dependence, tumors, cells, precedes
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