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Increased levels of stromelysin-1 and tissue inhibitor of metalloproteinases1 in sera from patients with rheumatoid arthritis.

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ARTHRITIS & RHEUMATISM Volume 38
Number 7, July 1995, pp %9-975
0 1995, American College of Rheumatology
969
INCREASED LEVELS OF STROMELYSIN-1 AND
TISSUE INHIBITOR OF METALLOPROTEINASES-1 IN
SERA FROM PATIENTS WITH RHEUMATOID ARTHRITIS
YASUO YOSHIHARA, KEN’ICHI OBATA, NOBORU FUJIMOTO, KYOKO YAMASHITA,
TARO HAYAKAWA, and MASAYUKI SHIMMEI
Objective. To evaluate the efficacy of stromelysin-1
(matrix metalloproteinase-3 [MMP3]) and tissue inhibitor of metalloproteinases-1 (TIMP-1) in serum as
markers for joint inflammation in rheumatoid arthritis
(RA).
Methods. Levels of both macromolecules in sera
from 97 healthy controls, 109 patients with RA, and 47
patients with osteoarthritis (OA) were measured by
respective 1-step sandwich enzyme immunoassays. In
the patients with RA, serum levels of MMP-3 and
TIMP-1 were investigated in relation to laboratory and
clinical measures of disease activity. In addition, the
relationships between serum and synovial fluid (SF)
levels in paired samples from individual patients were
examined.
Results. Serum levels of both MMP-3 and
TIMP-1 in RA patients were significantly higher than
those in OA patients and in healthy controls (P <
0.001), and were shown to correlate with traditional
systemic markers of inflammation including the erythrocyte sedimentation rate and C-reactive protein level,
and with the Lansbury articular index. In addition, it
was noted that serum levels of MMP-3 correlated with
the corresponding values in paired SF samples obtained
concurrently from patients with RA (r, = 0.588, P <
Supported in part by the grant for rheumatoid arthritis from
the Ministry of Health and Welfare of Japan.
Yasuo Yoshihara, MD, Masayuki Shimmei, MD, PhD:
National Defense Medical College, Tokorozawa, Japan; Ken’ichi
Obata, PhD, Noboru Fujimoto, PhD: Fuji Chemical Industries,
Ltd., Takaoka, Japan; Kyoko Yamashita, MS, Taro Hayakawa,
MD, PhD: School of Dentistry, Aichi-Gakuin University, Nagoya,
Japan.
Dr. Shimmei is deceased.
Address reprint requests to Yasuo Yoshihara, MD, Department of Orthopaedic Surgery, National Defense Medical College,
3-2 Namiki, Tokorozawa, Saitama, 359, Japan.
Submitted for publication June 24, 1994; accepted in revised form January 25, 1995.
0.001), while such correlations were not found for
TIMP-1 levels.
Conclusion. Our results support the notion that
levels of both MMP-3 and TIMP-1 in RA patient sera
are increased in association with inflammation. Furthermore, the level of MMP-3 in serum provides a particularly useful marker of inflammatory activity in the joints
of patients with RA.
Synovial inflammation, which consequently
causes destruction of articular cartilage via an extrinsic pathway, is a common condition associated with a
variety of arthritides, including rheumatoid arthritis
(RA) and osteoarthritis (OA). Although the precise
mechanism of cartilage destruction is not fully understood, many classes of proteinases, which are produced by synovial cells, macrophages, neutrophils,
and also by chondrocytes, are thought to play a critical
role in the degradation of cartilage matrix (1-4). Indeed, it has been reported that synovial fluid (SF)
contains an excess of proteinases during inflammatory
arthritis (5-7).
Stromelysin-1 (matrix metalloproteinase-3
[MMP-3; EC 3.4.24.17]), a neutral proteinase with a
broad substrate range, is believed to be a key enzyme
during cartilage destruction (8). It is capable of degrading many components of the extracellular matrix,
including cartilage aggrecan, types 11, IV, IX, and XI
collagen (9), laminin, and fibronectin, and also of
activating interstitial procollagenase (proMMP-1)
(10,ll) and progelatinase B (proMMP-9) (12). It is well
established that the biologic enzymatic activity of
metalloproteinases (MMPs) in connective tissue is
suppressed by tissue inhibitors of metalloproteinases
(TIMP-1 and TIMP-2), which interact with activated
MMPs with a 1:1 stoichiometry.
Recently developed one-step enzyme immuno-
YOSHIHARA ET AL
970
assay (EIA) systems using specific monoclonal antibodies against MMP-3 and TIMP-1 have made it
possible to detect their respective antigens in body
fluids. Using these methods, the levels of MMP-3 and
TIMP- 1 and the ratio of MMP-3 to TIMP- 1 were found
to be increased in SF from patients with acute pyrophosphate arthritis (13), primary OA (13), posttraumatic arthritis (13,14), and, most significantly, RA
(6,15,16). It has been suggested that levels of this
enzyme and inhibitor in SF have prognostic value with
regard to joint inflammation and/or activity of cartilage
destruction.
Elevated serum levels of TIMP-1 have been
previously reported in patients with RA (17,18). However, published studies of MMP-3 levels in the sera of
RA patients have not been performed except for our
earlier study (19), in which only a small number of
patients were investigated. In addition, previous studies have not examined the interrelation of these macromolecules in sera either with clinical and laboratory
indicators of diagnosis or disease severity or with the
corresponding levels in SF.
In the present study, we measured the levels of
MMP-3 and TIMP-1 in sera from patients with RA and
OA compared with healthy controls, using respective
1-step sandwich EIAs. We investigated the relationship of these levels to systemic indicators of inflammatory activity and to the corresponding values in SF,
and assessed them as markers for joint inflammation in
I2A. Our results suggest that serum levels of MMP-3,
in particular, provide a useful marker of inflammatory
activity in RA joints.
PATIENTS AND METHODS
Patients. One hundred nine patients with RA, 47
patients with knee OA (as classified at the Department of
Orthopaedic Surgery, National Defense Medical College
Hospital, Tokorozawa), and 97 healthy controls with no
evidence of joint damage or joint pain were studied. All
arthritis and control groups were selected without respect to
the patients’ sex or age. General and clinical characteristics
of the patients and controls are summarized in Table 1.
Diagnosis of patients with RA was based on the
American College of Rheumatology (formerly, the American
Rheumatism Association) 1987 revised criteria (20). Ten
patients were classified in stage I, 34 in stage 11, 26 in stage
111, and 39 in stage IV, according to the Steinbrocker criteria
for determination of RA progression (21).
All patients with RA were treated with nonsteroidal
antiinflammatory drugs (NSAIDs). Forty-four of these patients also received low-dose steroid treatment (prednisolone, maximum 10.0 mg/day). Also, several patients in this
group were receiving disease-modifying antirheumatic
Table 1. Characteristics of the patients and control subjects
Study group (n)*
RA
All patients (109)
Female (92)
Male (17)
Stage I(10)
Stage I1 (34)
Stage 111 (26)
Stage IV (39)
OA
All patients (47)
Female (42)
Male (5)
..
Control
All Subjects (97)
Female (53)
Male (44)
Age, yearst
Disease duration,
yearst
57 (23-82)
56.5 (27-82)
57 (23-74)
49.5 (23-64)
55 (23-82)
57 (27-76)
59 (3679)
7.0 (0.25-40.0)
7.5 (0.25-40.0)
6.0 (0.5-27.0)
1.5 (0.25-4.0)
4.0 (0.5-22.0)
10.0 (2.0-30.0)
14.5 (7.040.0)
69 (4485)
69 (44-85)
68.5 (67-75)
10.0 (0.5-30.0)
1 I .5 (0.5-30.0)
9.5 (2.0-25.0)
45 (23-72)
50 (23-72)
44 (27-63)
~~~~~
* Rheumatoid arthritis (RA) stages were assessed according to the
Steinbrocker criteria (21) (no. of femaledno. of males = 8/2 in stage
I, 3113 in stage 11, 17/9 in stage 111, and 36/3 in stage IV). OA =
osteoarthritis.
t Values are the median (range).
drugs, i.e., sulfasalazine (n = 15), D-penicillamine (n = lo),
bucillamine (n = 14), sodium aurothiomalate (n = 19), or
auranofin (n = lo), and 11 were receiving methotrexate,
either alone or in combination with steroid.
Knee OA was diagnosed from clinical and radiologic
evaluations, based on the American College of Rheumatology criteria (22). Patients who presented with obvious joint
injury and with generalized OA were excluded from the
study. Nineteen of the 47 patients with OA were receiving
various NSAIDs for knee pain.
Patients with RA or OA were not treated with intraarticular injection of steroids, chondroitin polysulfate, or
hyaluronic acid for at least 1 month prior to this study.
Collection and preparation of samples. Ten milliliters
of blood was collected without additives from all patients
and controls. Serum was separated and stored at -80°C until
use. At the time of blood collection, SF was also aspirated
from the knee joint of patients with RA (n = 41) and OA (n =
34) who reported knee pain and swelling. The SF samples
were collected into sterile plastic tubes without additives and
centrifuged at 10,OOO revolutions per minute for 20 minutes
at 4°C. Cell-free supernatants were stored at -80°C prior to
use in subsequent assays.
Quantitation of MMP-3 and TIMP-1 by EIA. Levels
of MMP-3 in sera and SF were determined by a 1-step
sandwich EIA system as previously described (19), with
minor modifications. Briefly, the assay system used a simultaneous immunoreaction of a solid-phase monoclonal antibody with a horseradish peroxidase-labeled Fab’ fragment
of another monoclonal antibody raised against human
MMP-3. MMP-3 was purified from the conditioned medium
of human skin fibroblast cells (NBlRGB) in its precursor
form, consisting of a 57-kd nonglycosylated form with a
small amount of a 59-kd glycosylated form. After the immunoreaction, peroxidase activity was determined, and MMP-3
97 1
SERUM STROMELYSIN-1 AND TIMP-1 IN RA
Table 2. Serum and synovial fluid (SF) levels of stromelysin- 1 (matrix metalloproteinase-3 [MMP-3])
and tissue inhibitor of metalloproteinases-1 (TIMP-1) in rheumatoid arthritis (RA) patients, osteoarthritis (OA) patients, and healthy controls
MM PJ , ng/ml
Sample source
(n)
TIMP-1, ng/ml
Mean ? SD
(range)
Median
*
Median
Mean SD
(range)
~
RA serum
Female (92)
161.5*
Male (17)
183*
OA serum
Female (42)
38*
Male ( 5 )
51
Control serum
Female (53)
26$
Male (44)
57.5
RA SF (41)
84.2 x 1035
OA S F (34)
10.7 x 103
303.9 -t 382.5
(51,870)
224.3 f 147.0
(36-548)
41.4 f 15.4
(572)
51.6 2 15.9
(33-68)
28.2 2 12.5
(168)
57.1 -t 22.4
(5101)
98.4 -t 75.9 x 103
(0.9-282 X lo3)
14.7 f 11.3 X lo3
(1.4-47 x 103)
175*
189t
153
154
157.5
157.5
9115
51 1
186.5 f 50.7
(107-376)
185.1 f 38.7
(1 18-253)
157.3 f 31.6
(99-249)
152.4 f 23.9
(120-175)
154.0 ? 23.7
(92-212)
151.1 f 30.0
(99-2 16)
1,032 f 500.6
(329-2,490)
523.1 f 258.2
(228-1,228)
* P < 0.001 versus serum from controls of the same sex.
t P < 0.01 versus serum from controls of the same sex.
$
§
P < 0.001 versus serum from male controls.
P C 0.001 versus OA SF.
levels were calculated from a standard curve using the 57-kd
human proMMP-3. Immunoreactivity of the 57-kd proenzyme to the monoclonal antibodies was -2-fold higher than
that of the 59-kd proenzyme. Approximately 95% of serum
MMP-3 exists as the 57-kd nonglycosylated form (19). We
thus further separated the 2 proenzymes by column chromatography on concanavalin A-Sepharose (19) and used the
57-kd proenzyme as the protein standard in this experiment.
The sensitivity of the assay system was 0.46 ng, and linearity
was observed between 0.63 and 20 ng. The EIA system for
MMP-3 quantitatively measures not only the precursor form
of MMP-3, but also the active form of MMP-3, as well as
MMP-3 complexed with TIMP-1 or TIMP-2 (19).
TIMP-1 levels in sera and SF were also quantitated
by our I-step sandwich EIA system (17). This was done by
immunoreaction of a solid-phase monoclonal antibody with a
horseradish peroxidaselabeled Fab' fragment of another
monoclonal antibody raised against bovine TIMP-1 (23). The
assay system for TIMP-1 is capable of cross-reacting with
human TIMP-1 (17) and measuring both free TIMP-1 and
TIMP-1 complexed with MMP-1, gelatinase A (MMP-2),
MMP-3, gelatinase B (MMP-9), and proMMP-9 (24). The
sensitivity of the assay system for human TIMP-1 was
1.5 pg.
Other analyses. In patients with RA, the following
laboratory and clinical features were also determined: erythrocyte sedimentation rate (ESR), C-reactive protein (CRP)
level, rheumatoid factor (RF) level, duration of morning
stiffness, and Lansbury articular index (LAI) (25). ESR was
determined according to the Westergren method; CRP and
R F levels were determined by routine laboratory techniques,
using turbidimetric immunoassay and latex immunonephelometry, respectively. Normal values for CRP and R F are
<0.3 mg/dl and <40 IU/ml, respectively.
Statistical analysis. Differences between groups were
analyzed by the Mann-Whitney U test for unpaired variables. Correlations were sought using Spearman's rank
correlation coefficient. P values less than 0.05 were considered significant.
RESULTS
Serum levels of MMP-3 and TIMP-1 in RA
patients, OA patients, and healthy controls. Means f
SD, medians, and ranges of the MMP-3 and TIMP-1
values in serum from patients with RA and OA and
from healthy controls are summarized in Table 2.
In healthy controls, serum levels of MMP-3
were very low and remained within a relatively small
range. When sex differences in these levels were
examined in control subjects, serum levels of MMP-3
in men were found to be significantly higher than those
in women (P< 0.001). Sex differences with regard to
TIMP-1 levels were not observed in control subjects.
The median serum MMP-3 levels in both female
YOSHIHARA ET AL
972
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0
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0
0
0
8
T***
0
3
800
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3
250
W
O.O!
3
01
Cont
I
I1
I11
IV
1
Cont
I
I
I
111
Iv
I
RA Stage
RA Stage 2
A
I
I1
B
Figure 1. Serum levels of stromelysin-1 (matrix metalloproteinase-3 [MMP-31) (A) and tissue inhibitor of metalloproteinases-1 (TIMP-1) (B)
in patients with rheumatoid arthritis (RA) and in healthy controls (Cont). The patients with RA were classified into 4 groups according to the
degree of disease progression as determined by the Steinbrocker criteria (21). MMP-3 levels in RA patient sera, even in patients whose RA was
at the earliest stage, were shown to be higher than those in healthy controls, and appeared to increase as the disease progressed. In contrast,
the distribution of TIMP-1 levels in RA patient sera showed a different pattern, i.e., TIMP-1 levels in RA sera in patients whose disease was
at the earliest stage were similar to those in controls. Significant differences from control values were observed in patients with stage 11-IV RA.
Distributions of individual values are presented as box plots. Open circles represent values of outliers; bars above and below boxes represent
ranges of values other than outliers; ends of boxes represent twenty-fifth and seventy-fifth percentiles; horizontal bars in boxes represent the
medians in each group. * = P < 0.05; ** = P < 0.01; *** = P < 0.001, versus controls.
and male patients with RA were 3-6-fold higher than
those in the OA and control groups. In 84.8% of female
and 76.5% of male patients with RA, levels of serum
MMP-3 were elevated more than 2 SD above the mean
level in the respective control group. In addition,
serum MMP-3 levels in female OA patients were
significantly higher than those in female controls (P<
0.001). Sex differences in levels of MMP-3 were not
observed in RA or OA patients. Median TIMP-1 levels
in the sera of RA patients were also shown to be
significantly elevated compared with controls and with
OA patients, although the increase was less pro-
nounced than those observed for MMP-3 levels. A
significant correlation was observed between serum
MMP-3 values and serum TIMP-1 values in RA (r, =
0.263, P < 0.01).
Correlation of serum levels of MMP-3 and
TIMP-1 with RA disease progression and disease activity. Levels of MMP-3 in RA patient sera, even at early
stages of RA, were shown to be higher than those in
controls, and appeared to increase as the disease
progressed. In contrast, the distribution of TIMP-1
levels in RA sera showed a different pattern from that
of MMP-3. TIMP-1 levels in RA sera at the earliest
973
SERUM STROMELYSIN-1 AND TIMP-1 IN RA
stage of disease were similar to those of controls,
whereas significant differences were observed at
stages 11-IV (Figures 1A and B).
When the relationship of MMP-3 and TIMP-1
levels to systemic markers of inflammation in RA were
examined, positive correlations with the ESR, CRP,
RF, and LA1 were recognized (Table 3). The calculated Spearman's rank correlation coefficient demonstrated that serum MMP-3 levels correlated more
closely than did TIMP-1 levels with conventional
markers of RA, except for RF values. Neither MMP-3
nor TIMP-1 was shown to have any correlation with
duration of morning stiffness.
Relationship between serum and SF levels of
MMP-3 and TIMP-1. Levels of MMP-3 and TIMP-1 in
SF from the knee joints of RA and OA patients are
shown in Table 2. It was found that the median SF
MMP-3 levels were -500-fold higher than median
serum MMP-3 levels, whereas TIMP-1 levels in SF
were on the same order as those in sera. Both MMP-3
and TIMP-I levels in S F from patients with RA were
significantly higher than those in OA S F (P < 0.001),
similar to the comparisons observed in sera.
Correlations between serum levels and SF levels of MMP-3 and of TIMP-1 were also examined. A
significant correlation was observed only for serum
and SF levels of MMP-3 in patients with RA (r, =
0.588, P < 0.001) (Figure 2); TIMP-1 levels in RA
showed no correlation (r, = 0.106).
DISCUSSION
In previous studies, elevated levels of MMP-3
and TIMP-1 were detected in S F from RA patients
compared with levels in OA patients (6,15,16), suggesting increased release from highly inflamed synovial tissue. Lohmander et a1 (13,14) demonstrated a
Table 3. Correlation (Spearman's rank correlation coefficient [rJ)
of serum levels of MMP-3 and TIMP-1 with clinical and laboratory
markers of disease activity in RA*
MMP-3
ESR
CRP
RF
LA1
A M stiffness
TIMP-1
rs
P
rs
0.638
0.559
0.277
0.579
-0.081
<0.001
<0.001
0.372
0.510
0.507
0.307
-0.109
<0.05
<0.001
NS
P
<0.~01
<0.001
<O.Ool
<0.01
NS
* ESR = erythrocyte sedimentation rate; CRP = C-reactive protein;
RF = rheumatoid factor: LA1 = Lansbum articular index: NS = not
significant. See Table 2 for other definitibns.
3001
- 250
1
Y
1
v
.h
201--"A
a
w -
0
0
C
0
.
500
.
.
,
I
.
1000
.
I
.
....
1500
2000
Serum MMP-3 (ng/ml)
Figure 2. Correlation between the serum and synovial fluid levels
of MMP-3 in patients with RA. A significant correlation was found
(Spearman's rank correlation coefficient = 0.588, P < 0.001). See
Figure 1 for definitions.
relative increase in levels of MMP-3, compared with
TIMP-1, in SF from patients with OA, posttraumatic
arthritis, and crystal-induced arthritis. Hence, an imbalance of MMP-3 and TIMP-1 in SF may be diagnostic or even prognostic of joint inflammation and consequent tissue-degrading activity. We (17) and others
(18) have detected increased levels of TIMP-1 in RA
sera. We have developed a 1-step sandwich EIA for
MMP-3. Our pilot study in which a limited number of
patients were examined using this method suggested
increased levels of MMP-3 in RA sera (19).
In the present study, we have demonstrated
that serum levels of MMP-3 and TIMP-I in patients
with RA were significantly higher than those in OA
patients and healthy controls. We have also shown
ihat both values in RA patient sera significantly correlated with the ESR, CRP and RF levels, and LAI.
These results suggest that serum MMP-3 and TIMP-1
levels will be indicative of the degree of inflammatory
activity in RA. In addition, only for MMP-3 were
serum levels found to correlate with corresponding
levels in SF. S F levels Of MMP-3 in RA patients were
in the range of microgram quantities, which represents
YOSHIHARA ET AL
974
approximately a 500-fold excess when compared with
serum MMP-3 levels. It is conceivable that MMP-3 in
serum is derived primarily from inflamed joints.
TIMP-1 levels in sera from patients with RA
were shown to be significantly higher than those in OA
patients and healthy controls, but the differences were
smaller than those seen for MMP-3. In addition, levels
of TIMP-1 expressed as a ratio of the concentration in
SF to the concentration in serum (-5-fold) were less
elevated than those observed in similar comparisons
for MMP-3. If the rates of clearance of MMP-3 and
TIMP-I from SF to blood are similar, these results
indicate that TIMP-1 in sera may come from other
sources. Cooper et a1 (26) reported that the TIMP-1
found in sera may result from its release by platelets
during blood clotting, and other investigators reported
that TIMP-I levels in sera were 2-3-fold higher than
those observed in plasma (17,27).
A variety of serologic markers have been used
to monitor the degree of disease activity in RA, and
various new markers have been reported (28-31). In
this study, serum levels of MMP-3 were increased in
RA and were correlated with disease activity and also
with SF levels of MMP-3, whereas such a correlation
was not observed for TIMP-I. We therefore propose
that serum MMP-3 may be an additional serologic
marker indicative of joint inflammation and cartilagedegrading activity in RA.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
ACKNOWLEDGMENTS
The authors thank Dr. Peter Kowalski-Saunders and
Dr. Kazushi Iwata for reviewing the manuscript.
18.
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stromelysin, sera, level, increase, patients, inhibitors, arthritis, tissue, rheumatoid, metalloproteinase
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