Clinical Science (1982) 62,7 1-76
71
Synovial fluid and plasma fibronectin levels in
rheumatoid arthritis
D. L. S C O T T , M. F A R R , A. P. C R O C K S O N A N D K. W. WALTON
Department of Investigative Pathology, Rheumatism Research Wing, The Medical School, University of Birmingham,
Birmingham. U.K.
(Received 30 March123 June 1981; accepted 20 July 1981)
Summary
1. Plasma fibronectin levels were similar in 60
healthy subjects and 88 with rheumatoid arthritis.
2. In 42 patients with rheumatoid arthritis
synovial fluid fibronectin levels were significantly
higher than plasma levels (P< 0401). Intermediate fibronectin levels were found in synovial fluid
from six patients with psoriatic arthritis, eight
patients with osteoarthritis and seven with seronegative arthritis.
3. Plasma and synovial fluid fibronectin levels
were not related to indices of inflammatory
activity such as the erythrocyte sedimentation
rate, the Ritchie articular index or synovial fluid
cell counts. Nor did fibronectin behave as an
acute-phase protein.
4. Immunofluorescent studies showed that
fibronectin was adsorbed on fibrinous debris in
rheumatoid arthriticjoints.
5. These findings suggest that there is local
production of fibronectin by the synovium and
suggest that measurement of fibronectin levels in
the synovial fluid may serve as an indicator of the
tissue response to rheumatoid arthritis.
Key words: fibronectin,rheumatoid arthritis.
Introduction
Fibronectin, a high-molecular-weight glycoprotein, also known as cold insoluble globulin, is
widely distributed in the tissues, plasma and
Correspondence: Professor K. W. Walton,
Department of Investigative Pathology, The Medical
School, University of Birmingham, Birmingham, B15
2TJ, U.K.
6
0143-5221/82/010071-06$01.50/1
tissue fluids 11-31. It is a product of
mesenchymal cells and there has recently been
considerable interest in its role in both normal
and pathological states 141. Its ability to bind to
fibrin(ogen) and to collagen suggests that it may
have a major role in the tissue response to an
inflammatory stimulus. Rheumatoid arthritis is
characterized by fibrin deposition, fibrosis and
pannus formation, and we have recently shown, in
an immunohistochemical study [51, that fibronectin is present in the synovium in increased
amounts in rheumatoid arthritis and is related to
fibrin deposition and fibrosis. We now report a
detailed investigation of plasma and synovial fluid
fibronectin levels in rheumatoid arthritis and an
evaluation of the significance of these levels in
relation to clinical, immunochemical and haematological changes.
Patients and methods
Subjects studied
Eighty-eight consecutive patients with definite
or classical rheumatoid arthritis 161 attending a
rheumatology clinic gave plasma and serum
specimens. Synovial fluid specimens were collected from 62 additional patients requiring diagnostic or therapeutic joint aspirations. The
majority of these had rheumatoid arthritis by the
same criteria, but some had oestoarthritis, seronegative arthritis, as defined by Wright & Moll
171, or psoriatic arthritis. Control plasma and
serum samples were obtained from 60 healthy
donor subjects attending a blood transfusion
centre. All subjects in the study gave informed
consent for specimens to be collected. Details of
the patients and controls are given in Table 1.
@ 1982 The Biochemical Society and the Medical Research Society
D. L. Scott et al.
12
TABLE1. Details ofpalienls and control subjects
n
Specimens
Plasma
Controls
Rheumatoid arthritis
Synovial fluid
Rheumatoid arthritis
Osteoarthritis
Seronegative arthritis
Psoriatic arthritis
Mean age
(years) (range)
Total
Sex
(M/F)
60
88
32/28
31/57
32.5 (18-64)
57.3 (31-32)
41
8
7
6
11/30
3f5
4/3
3/3
58.1 (33-80)
63.4(57-83)
41.8 (28-88)
57,0(47-71)
Characteristics of arthritic patients
The duration of early morning stiffness and
the Ritchie index [81 were recorded. The
haemoglobin concentration, leucocyte count,
platelet count and erythrocyte sedimentation rate
(Westergen) were measured. Tests for IgM
rheumatoid factor (sheep cell agglutination titre)
and antinuclear factor (by indirect immunofluorescence) were performed.
CoUection of specimens
Plasma and synovial fluid were collected
aseptically into sterile tubes and anticoagulated
with 1% (w/v) disodium ethylenediamine-tetraacetic acid (EDTA) and then centrifuged (10 min
at 1500 g) to remove cellular and other material.
Serum was similarly collected. Specimens were
collected in the morning (10.00-12.00 hours).
Samples were immediately frozen at -8OOC until
analysed. Additional synovial fluid specimens
were analysed (see below) without centrifugation
or storage. For immunochemical analyses, synovial fluid specimens were incubated at 24OC for
15 min with 5% (w/v) hyaluronidase at 1500
units/ml (ovine: Fisons Ltd) after thawing.
Tests on synovialfluid
Acid phosphatase [orthophosphoric monoester
phosphohydrolase (acid optimum): EC 3.1.3.21
was measured as described by Roy et al. [91 and
5’-nucleotidase (5 ’-ribonucleotide phosphohydrolase; EC 3.1.3.5) by the method of Persijn et al.
[lo1 with synovial fluid which had not been
frozen. Similarly, synovial fluid cell counts were
performed in 5 1 subjects, and in six patients with
rheumatoid arthritis smears were examined by
histological and immunohistological methods as
detailed below.
Purification of fibronectin and preparation of
anti-Jibronectinantiserum
Human fibronectin was isolated from plasma
by atlinity chromatography with gelatin coupled
to cyanogen bromide-treated Sepharose 4B
(Pharmacia Ltd.) as described by Engvall &
Ruoslahti [ l l ] and modified by Dessau et al.
1121. The fibronectin was further purified by the
removal of minor contaminating plasma proteins
by chromatography on a Sephacryl S300
(Pharmacia Ltd) column and elution with a
buffer containing Tris (0.05 mol/l)/NaCl (0.1
mol/l) adjusted with HCl to pH 7.6. The purity of
the final product was assessed in several ways: on
sodium dodecyl sulphate (SDS)/polyacrylamidegel electrophoresis it gave a single band (mol. wt.
220 OOO) when run on 5% (w/v) gels in reducing
conditions: in two-dimensional immunoelectrophoresis performed as described by Clarke &
Freeman [ 131 it gave a single protein peak with
antiserum to whole human serum (Wellcome).
The purified fibronectin was homogenized in
Freund’s complete adjuvant and injected subcutaneously and intramuscularly into rabbits.
Subsequent injections were made intracutaneously without adjuvant in a dosage
schedule described previously by Soothill 1141.
When necessary, antiserum produced by this
method was rendered monospecific by absorption
of the antisera with the fibronectin-free supernatant from the first step of the isolation
procedure as absorbant. The final antisera obtained were monospecific when tested with serum
or plasma on double immunodiffusion and with
both one-dimensional immunoelectrophoresis
performed in 1% (w/v) agar (containing barbiturate buffer at ionic strength 0.05 at pH 8.6) using
a modification of the technique of Scheidegger
[ 151 and two-dimensional imrnunoelectrophoresis. The antisera gave single precipitin arcs
producing a ‘reaction of identity’ with two
reference antisera: (a) a commercial antiserum
obtained from Hoechst Ltd, and (b) an antiserum to plasma fibronectin kindly provided by
Dr J. Bums, Department of Pathology, University of Oxford.
Estimation offibronectin levels
The concentration of fibronectin in plasma and
synovial fluid was measured by both ‘rocket’
immunoelectrophoresis [ 161 and single radial
immunodiffusion 1171. Both methods gave similar
results with coefficients of variation of less than
3%. Agarose (Indubiose) was used for both
Fibronectin in arthritis
techniques in a buffer containing barbitone (0.05
mol/l) with EDTA (0405 mol/l) at pH 8.2 to
minimize fibrinogen precipitation 1181. Plasma
fibronectin levels measured with this assay
system were similar to those previously reported
by Mosesson & Umfleet 1191 and Matsuda et al.
131.
73
f
501
Other immunochemical investigations
Serum and synovial fluid were examined for
levels of immuno'globuliis (Ig) G, A and M by
single radial immunodiffusion 1171. In each case
monospecific antiserum and highly purified protein standards (from Department of Immunology, University of Birmingham) or pooled
serum standards were used. C-reactive protein
and haptoglobin in these specimens were estimated as described previously 1201.
ImmunoJuorescence studies
Air-dried synovial fluid smears were fixed in
cold acetone (4OC) for 60 s and then examined
by the indirect immunofluorescence technique as
described by Nairn 1211. They were treated with
the rabbit anti-(human fibronectin) antiserum and
then with fluorescein-labelled sheep anti-(rabbit
immunoglobulin) antiserum. Control smears were
examined after treatment with both nonimmunized rabbit serum followed by fluoresceinlabelled sheep anti-(rabbit immunoglobulin) and
after treatment with the latter antiserum alone.
Smears were subsequently stained with phosphotungstic acid/haematoxylin for light microscopy.
Immunofluorescence was performed with a Zeiss
S 14 indirect-light fluorescence microscope.
?=rrults
Plasma and synovialfluidjibronectin (Fig. 1 )
Plasma fibronectin levels were similar in
patients with rheumatoid arthritis (mean 0.35 g/l,
SD 0.11; n = 88) and control subjects (mean
0.33 g/l, SD 0.1 1; n = 60), as shown in Fig. 1,
and were not significantly different ( P > 0.10;
Student's t-test). Although synovial fluid fibronectin levels showed a comparatively wide
scatter, patients with rheumatoid arthritis (mean
0.71 g/l, SD 0.41; n = 41) had significantly
higher levels ( P < 0.001; Mann-Whitney U-test)
in comparison with plasma levels (in patients and
control subjects). Intermediate values were found
in synovial fluids from patients with osteoarthritis (mean 0.50 g/l, SD 0.20;n = 8), sero-
'0
c
RA
Plasma
RA
OA
SN
PA
Synovial fluid
FIG. 1. Fibronectin levels in plasma and in synovial
fluid for control healthy subjects (C), rheumatoid
arthritis (RA), osteoarthritis (OA), seronegative
arthritis (SN) and psoriatic arthritis (PA). Horizontal
bars represent the mean values for each group, and
broken lines show f 2 SD above and below the mean
for controls.
negative arthritis (mean 0.51 g/l, SD 0.19; n = 7)
and psoriatic arthritis (mean 0-60g/l, SD 0.11;
n = 6).
A comparison of plasma and synovial fluid
fibronectin levels in specimens taken concurrently in patients with rheumatoid arthritis
confirmed that synovial fluid levels were higher
than plasma levels in the group as a whole
( P < 0.01; Wilcoxon rank-sum test). But individual results (Fig. 2) showed that this pattern
was not of uniform occurrence in individual
patients, and there was no correlation between
plasma and synovial fluid fibronectin levels.
Relation of plasma Jibronectin to disease activity
in rheumatoid arthritis
Plasma fibronectin levels were unrelated to
most indices of disease activity in rheumatoid
arthritis (Table 2) nor to drug therapy, and there
was no evidence that fibronectin behaved like
known acute-phase reactants (C-reactive protein
or haptoglobin). Plasma fibronectin levels were
also unrelated to the presence or absence of
rheumatoid factor, IgG antinuclear factor or to
the respective titres of these autoantibodies.
D. L. Scott et al.
TABLE3. Relationship of synovialfluidfibronectinto serum
acute-phase proteins in rheumatoid arthritis: patients with
the seven highest fibronectin levels compared to those with
the lowest levels
0
Group
High synovial
fluid fibronectin
Patient
no.
I
2
3
4
5
0
6
7
0
Mean
Low synovial
fluid fibronectin
0
Serum
Serum
C-reactive haptoglobin
(gh)
protein
(do
(mg/l)
1.83
1.81
1.59
1.25
1.25
1.04
0.95
1.39
7
46
3
14
32
51
10
23.3
1.18
2.12
I .94
I .40
1.73
3.13
1.92
1.92
0.38
0.34
0.34
0.27
0.24
I04
38
9
1 I6
20
26
I64
68. I
3.38
1.53
1.12
4.48
1.73
2.18
3.15
2.5 I
0
0
O
Synovial
fluid
fibronectin
I O
0
.
I
I
Mean
FIG. 2. Fibronectin levels in matched plasma ( 0 )
and synovial fluid (0) specimens taken concurrently
from 18 patients with rheumatoid arthritis. Mean
synovial fluid levels were significantly higher (P <
0.01) than plasma levels for pooled results (as for
data in Fig. 1; but note variations from this pattern
in individual patients).
TABLE 2. Relationship of plasma fibronectin levels to
direrent parameters of disease activity in rheumatoid
arthritis
n = Number of patients. N.S., Not significant.
Parameter
Duration of early morning stiffness
(min)
Ritchie index
Erythrocyte sedimentation rate
(mm in first hour)
C-reactive protein (mg/l)
Haptoglobin (g/l)
k G (g/I)
IgA (g/O
k M (dl)
Haemoglobin (g/dl)
x Leucocyte count (numberh)
x Platelet count (number/l)
n
r
P
88
-0.186
N.S.
88
85
-0.210
(0.05
N.S.
85
86
86
86
86
85
85
81
-0.029
0,034
-0.135
-0.I27
-0.131
0.257
0.082
-0.063
0.016
N.S.
N.S.
N.S.
N.S.
N.S.
<0.05
N.S.
N.S.
-
Relation between jbronectin levels and other
changes in synovialjluid
The level of fibronectin measured in joint fluid
8
9
10
II
12
13
14
0.15
0.15
0.27
was unrelated to polymorphonuclear leucocyte,
lymphocyte or synovial cell counts. A correlation of relatively low statistical significance with
the erythrocytes in joint fluid ( r = +0.300;
n = 51; P < 0.05) was of a similar order to the
equivocal relation found between plasma fibronectin and haemoglobin.
Synovial fluid fibronectin levels showed no
overall significant correlation with immunoglobulin or acute-phase protein levels, nor with
the activity of two enzymes (5’-nucleotidase and
acid phosphatase) in the fluid. Nor was there a
relationship to most systemic indices of disease
activity or drug therapy. But comparing the
patients with the seven highest fibronectin levels
in joint fluid with a similar number of patients
with the lowest levels, in relation to mean values,
there appeared to be an inverse relation between
levels of synovial fluid fibronectin and of either
serum C-reactive protein or haptoglobin (Table
3). However, this could not be substantiated by
formal analysis of the data by Wilcoxon’s
rank-sum test (P> 0.10).
Fibronectin in synovial smears
Amorphous acellular particles and others
which were fibrillar in shape gave positive
immunofluorescent staining for fibronectin. When
the same smears were stained with phosphotungstic acid/haematoxylin this material gave the
characteristic dark blue reaction of fibrin.
Fibronectin was not demonstrable in or on
Fibronectin in arthritis
the surface of the cells in these smears by
immunofloorescence.
Discussion
In confirmation of a report by Fryand et al. t221
we have found the plasma level of fibronectin in
uncomplicated rheumatoid arthritis to be similar
to that found in health. However, there is
evidence [41 that, unlike most other plasma
proteins, fibronectin is synthesized, not in the
liver but peripherally by connective tissue cells. It
has been suggested [23, 241 that plasma fibronectin originates as the secretory product of
fibroblasts, since plasma fibronectin is immunologically closely related to the cell membranerelated protein produced by these cells and
released into their environment. If this is correct,
it might be expected that plasma levels would
only be increased with widespread and severe
involvement of connective tissues throughout the
MY.
In contrast, the raised levels of fibronectin in
synovial fluid in rheumatoid arthritis (and, to a
lesser extent, in other arthritides), which we now
report, may be accounted for by a localized
increase in production of this glycoprotein actually
at the site of the articular disease. Hence the level
of fibronectin in the synovial fluid may possibly
serve as an indicator of the stimulation of
synovium by disease, unlike indirect tests such as
the erythrocyte sedimentation rate, or the levels
of acute-phase reactants which are dependent on
increased protein synthesis by the liver in
response presumably to more generalized stimuli.
Our results establish not only that synovial
fluid fibronectin levels are unrelated to overall
indices of inflammatory activity in rheumatoid
arthritis, but also that no correlation can be
shown with synovial fluid polymorphonuclear
leucocyte counts or with 5-nucleotidase levels,
which reflect inflammation within the joint [25,
261. The weak relationship we have found
between fibronectin levels and the erythrocyte
count in synovial fluid is not readily explicable
and needs further study.
Our previous studies of the immunohistological distribution of fibronectin in the synovium
[5] showed that, although it was immunologically distinct from fibrin or fibrinogen, it was often
codistributed with fibrin deposited on the surface
of synovial villi or on ‘rice-bodies’ taken from
rheumatoid joints. This codistribution was
assumed to occur because of adsorption of
fibronectin on fibrin, in keeping with the strong
avidity which is known to be characteristic of the
interaction between these two proteins [271.
75
From examination of the particulate deposits in
synovial fluid from some of our patients with
rheumatoid arthritis we now find this codistribution in very early fibrin strands and
amorphous deposits in the fluid. Our previous
work had also shown fibronectin to be present
within, and presumably synthesized by, fibroblasts and synovial cells (and in addition to be
associated with early immature collagen, but not
fully formed fibrous tissue). These latter observations suggest fibronectin may play a transient
but possibly important part in the structural
organization of tissues concerned with healing
and repair in chronically involved joints.
Fibronectin does not serve as a yardstick by
which to measure ongoing activity in a joint. But
its presence in increased concentrations relative
to plasma in synovial fluid may be of significance
in relation to the outcome of the arthritic process.
Electron-microscopical studies have divided synovial cells into A (macrophage-like) and B
(fibroblast-like) cells 1281. It has been suggested
that the interaction of fibronectin with nonbacterial particulate material [291 opsonizes the
subsequent uptake of such material by
phagocytic cells. We have demonstrated fibronectin on fibrin strands and amorphous deposits
in synovial fluid. The fate of these deposits is
uncertain but the possibility that fibronectin, a
product of the fibroblast-like synovial B cells,
may act as an opsonizing factor for macrophages
derived from synovial A cells is an hypothesis
that merits further study. It may explain the role
of fibronectin in the acute phase of joint disease
as that of facilitation of the removal and disposal
of debris and detritus from the joint space.
In conclusion, therefore, it would seem that the
local production of fibronectin with arthritic
joints may influence either the resolution, or the
organization and repair, of intra-articular structures (the former process being most evident in
acute disease and the latter in the healing or
chronically affected joint). These dual aspects of
fibronectin’s role in modifying the response
characteristic of a potentially chronic and disabling disease like rheumatoid arthritis seem
worthy of continued study.
Acknowledgments
We acknowledge the help given to us in various
aspects of this study by Dr C. F. Hawkins, Dr D.
Felix-Davies, Dr J. P. Delamere and Dr R.
Ibbotson. We are grateful for support from the
Central Birmingham Health District Endowment
Fund. M. F. is an Arthritis and Rheumatism
Council Fellow. We thank Mr R. A. Crockson,
76
D. L. Scott et al.
Department of Immunology, University of
Birmingham, for measuring C-reactive protein
levels.
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