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Somatostatin-induced modulation of inflammation in experimental arthritis.

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ARTHRITIS & RHEUMATISM
Vol. 38, No. 11, November 1995, pp 1687-1693
0 1995, American College of Rheumatology
1687
SOMATOSTATIN-INDUCED MODULATION OF INFLAMMATION IN
EXPERIMENTAL ARTHRITIS
MARC0 MATUCCI-CERINIC, FRANCESCO BORRELLI, SERGIO GENERINI, ALFRED0 CANTELMO,
ISABELLA MARCUCCI, FABRIZIO MARTELLI, PAOLO ROMAGNOLI, STEFAN0 BACCI,
ANGEL0 CONZ, PAOLO MARINELLI, and SIMONE MARABINI
Objective. To study the antiinflammatory effect of
different doses of intraarticular somatostatin in experimental arthritis in rabbits.
Methods. Chronic arthritis was induced by a
single injection of fibrin into the knee joint of rabbits
previously sensitized to this antigen. The effects of
sequential intraarticular injections of somatostatin into
the rabbit knee, at doses of 500,750,and 1,000 pg, were
monitored by measuring knee joint circumferences and
hematologic parameters. The measurements were compared with those obtained following use of triamcinolone
acetonide and placebo. At the end of the experiments,
the knee joints were examined histologically.
Results. Somatostatin treatment induced a statistically significant and dose-related reduction of knee
joint swelling. This effect was shorter than that produced by triamcinolone acetonide; however, the antiinflammatory activity elicited by successive doses of triamcinolone acetonide declined both in extent and
duration, while the effects of somatostatin remained
unchanged at each successive treatment. Histopathologic observations showed that both somatostatin and
triamcinolone acetonide reduced the inflammatory signs
in the joint structures, although triamcinolone acetonide
appeared to be more effective.
Conclusion. These findings suggest that somatostatin exerts an antiinflammatory effect in this model
of experimental arthritis and may represent a valid and
Marco Matucci-Cerinic, MD: University of Cagliari, Cagliari, Italy; Francesco Borrelli, BS, Alfred0 Cantelmo, Isabella
Marcucci, Fabrizio Martelli: Research Institute “C. Serono SpA,”
Ardea, Rome, Italy; Sergio Generini, MD, Paolo Romagnoli, MD,
Stefan0 Bacci, BS, S h o n e Marabini, MD: University of Florence,
Florence, Italy; Angelo Conz, DVM, Paolo Marinelli, DVM: Biomedical Research Institute “A. Marxer” (RBM), Ivrea, Turin, Italy.
Address reprint requests to Marco Matucci-Cerinic, MD,
Istituto di Clinica Medica IV, viale Pieraccini 18, 50139-Florence,
Italy.
Submitted for publication December 27, 1994; accepted in
revised form June 13, 1995.
safer alternative to corticosteroids for intraarticular
therapy of arthritis.
Somatostatin is a ubiquitous undecatetrapeptide that is widely distributed throughout the central
nervous system (1). It was first isolated in the hypothalamus (2) and is known to inhibit the hypophysial
release of growth hormone, thyrotropin-releasing hormone, and prolactin (3). In the peripheral nervous
system, somatostatin is present in catecholaminecontaining fibers and in sensory terminals, together
with substance P (SP) and calcitonin gene-related
peptide. Evidence suggests that somatostatin is involved in the modulation of neurogenic inflammation
through the inhibition of SP release and SP-provoked
neurotransmission (4-6) and through the inhibition of
SP-induced neutrophil chemotaxis and GTPase activity (7). In addition, somatostatin can mediate nociception via a unique pathway different from that used
by SP (8).
Somatostatin has a wide range of biologic effects, mediated by receptors on a variety of target cells
( e l l ) . The major physiologic areas of somatostatin
action are 1) as a neurotransmitter, 2) on glandular
secretion, 3) smooth muscle contractility, and 4) cell
proliferation. Somatostatin induces a marked vasoconstriction, particularly in the splanchnic system, which
has led to its use in the treatment of esophageal
bleeding and hemorragic states. In vitro, somatostatin
has shown a unique capacity to inhibit the growth of
neoplastic cells. For this reason it has been used,
particularly in its analog form, in the treatment of
cancer (12). Somatostatin also affects the immune system, by inhibiting the Proliferation of human T lymphocytes (13), inhibiting the production of immunoglobulin by B lymphocytes (14), and reducing
interferon-y production by monocytes (15). It is able
to inhibit the release of histamine and leukotriene D4
1688
MATUCCI-CERINIC ET AL
from immunologically stimulated human basophils
(16), but not from mast cells (17).
The possibility of using somatostatin to treat
arthritis has been raised by reports of its analgesic
properties in animals (Borrelli F, Cantelmo A, MarteHi
F: unpublished observations) and humans (18,19). It
has been studied in rheumatoid arthritis (20), psoriatic
arthritis (21,22), and osteoarthritis (23). In experimental animal models, somatostatin has shown antiinflammatory activity in acute arthritis induced by urate
crystals in rats (24). Apparently there are no other
published studies that have evaluated the effect of
somatostatin on a chronic experimental arthritis, although previous reports in rats have demonstrated the
ability of some analogs to delay the onset of adjuvant
arthritis, thus limiting the seventy of inflammation (25).
The aim of this study was to test the efficacy of
intraarticular administration of somatostatin in experimental arthritis. Somatostatin was compared with a
drug currently used for the local treatment of arthritis
(triamcinolone acetonide) in an animal model of arthritis, i.e., antigen-induced arthritis in rabbits. In the
model, the arthritis develops following a single injection of fibrin into the knee joint of rabbits previously
sensitized to the same substance, and produces a
chronic self-perpetuating disease that closely resembles human rheumatoid arthritis (26).
MATERIALS AND METHODS
Animals. Male New Zealand white rabbits (initial
body weight 1.8-2.2 kg) from Charles River Italia (Calco,
Como, Italy), maintained under controlled environmental
conditions and fed ad libitum with a standard pellet diet and
water, were used for the experiments.
Substances tested. The commercial preparation of
somatostatin (Stilamin 3 mg/vial; Serono SPA, Rome, Italy)
was used for this study. Triamcinolone acetonide as its
commercial preparation, Kenacort-A Retard (Bristol-Myers
Squibb, Rome, Italy) was used as the reference drug.
Induction of arthritis. Arthritis was induced using the
method proposed by Lewis (27), with minor modifications.
Ninety-eight rabbits were initially sensitized with 1 ml of an
emulsion consisting of 10 mg bovine fibrin (Sigma, St. Louis,
MO) in equal volumes of sterile physiologic saline and
Freund’s complete adjuvant (FCA; Difco, Detroit, MI) containing 2 mg Mycobacterium tuberculosis H37RA (Difco).
This emulsion was injected intracutaneously into 5 separate
sites on the back of each animal. After 2 weeks, the animals
received a booster sensitization consisting of an emulsion of
5 mg bovine fibrin in 0.25 ml sterile saline and 0.25 ml FCA
injected intracutaneously into a single site on the back.
Seven days later, a sterile solution of 10 mg bovine
fibrin in 1 ml saline was injected into the left knee joint of
each rabbit under intravenous penthobarbitone sodium an-
esthesia (20 mglkg). The right knee joint received an equal
volume of sterile saline as a control. The day of the challenging injection of fibrin was considered to be day 0.
Drug administration. Eighteen days after the intraarticular injection of fibrin, when a stable monarticular arthritis
was obtained, 60 rabbits showing clear signs of the disease
(defined as joint swelling of more than 8 mm, measured by
joint circumference) were selected. The rabbits were randomly assigned, by computer-generated numbers, to 6 intraarticular treatment groups of 10 each, as follows: 1)
saline, 0.25 muknee joint (controls); 2) mannitol, 0.25 ml/
knee joint of a solution at 26.62 mg/ml (placebo), corresponding to the amount of mannitol contained in the highest
dose of Stilamin; 3) triamcinolone acetonide, 5 mg/knee joint
(in 0.25 ml); 4) somatostatin, 500 &knee joint (in 0.25 ml);
5) somatostatin, 750 &knee joint (in 0.25 ml); 6) somatostatin, 1,000 &knee joint (in 0.25 ml).
The first intraarticular injection was performed on
day 18. Additional injections were administered when the
effect of the drug was tapering and the circumference of the
joint reached the baseline value determined prior to treatment. The animals in groups 1 , 2 , 4 , 5, and 6 were treated on
days 18,25, 32, 39,50,60,74, and 81 following the challenge
injection. Rabbits in the third group received an intraarticular injection of triamcinolone acetonide on days 18, 39, 50,
60,74, and 81. On the same days, the contralateral (right)
knee joints of all animals were injected with an equal volume
of saline.
Data on animals that died prior to the end of the
study were not included in the analysis. At the end of the
study, there were 7 animals remaining in the control and
placebo groups and 8 in each of the test drug groups.
Clinical assessment. The extent of the inflammatory
reaction was evaluated by tape-measuring the knee joint
circumferences in all animals, to the nearest millimeter.
These measurements were performed just before the intraarticular challenge injection of fibrin (baseline) and repeatedly
thereafter, under local anesthesia with Ethyl Chlorure (Synthelabo SPA, Milan, Italy).
Starting at the time of pharmacologic treatment (day
18 post-challenge), measurements of left and right knee joint
circumferences were performed daily except Sunday. On the
days of drug administration, they were always performed
prior to injection. The differences between the drug-injected
(left) and the saline-injected (right) joints were recorded on
all observation days for every animal, and the circumference
variations of the drug-treated and control animals were
calculated.
Hematologic and hematochemical assessment. A series of hematologic parameters, including red blood cell
(RBC) count, total and differential white blood cell (WBC)
count, and erythrocyte sedimentation rate (ESR), and hematochemical parameters (serum protein electrophoresis) were
also determined, using standard laboratory methods, on the
animals prior to the experiment (baseline values), before the
first pharmacologic treatment, and 26, 54, and 82 days later
(days 13, 28, 55, and 88 post-challenge, respectively).
Histopathologic assessment. Following the last blood
sampling, and from 1 to 4 days after the last treatment, i.e.,
at the time of the maximal expected reduction of edema, the
rabbits were killed and their left knee joints were removed
SOMATOSTATIN IN EXPERIMENTAL ARTHRITIS
for histologic examination. Animals in the placebo and
control groups were killed on the fifth day after treatment.
The untreated right knee joints were also excised from 2
randomly selected animals in each experimental group.
The specimens, fixed in 10% buffered neutral formalin, were decalcified, embedded, cut with a microtome, and
stained with hematoxylin and eosin. They were examined by
light microscopy by 2 of the authors (PR and SB), who were
blinded to the treatment information. In order to evaluate the
degree of inflammation, an overall histologic score was
created using 8 different parameters: 1) synovial lining (0 =
simple, pavement epithelium; 1 = cuboidal cells and/or
bilayered epithelium one-third or less of visible surface; 2 =
bilayered epithelium on more than one-third, and/or multilayered epithelium on one-third or less, of visible surface;
3 = multilayered epithelium on one-third or more of visible
surface); 2) subsynovial cells (0 = rare cells; 1 = quite
numerous cells along one-third or less of visible surface; 2 =
quite numerous cells along more than one-third, and/or very
numerous cells along one-third or less, of visible surface; 3 =
very numerous cells along more than one-third of visible
surface); 3) leukocytic infiltrate (0 = no infiltration; 1 =
modest infiltration along one-half or less of visible surface;
2 = modest infiltration along more than one-half, and/or
marked infiltration along one-half or less, of visible surface;
3 = marked infiltration along more than one-half of visible
surface); 4) lymphoid follicles (1 point for each follicle);
5) vasculitis (1 point for every vessel with infiltration in the
wall thickness); 6) necrosis (1 point for each necrotic area);
7) fibrin deposits (1 point for each deposit); and 8) polynuclear giant cells (1 point for each cell).
Statistical analysis. The differences between the druginjected and the saline-injected knee joints on each observation day were used to calculate the variations of the joint
circumferences. Their peak values, i.e., the maximal reduction of edema as compared with baseline (the value immediately before drug injection), were subjected to one-way
analysis of variance. Scheffe's test was used to compare
effects in the drug- and placebo-treated groups. Student's
Days from atthntls mducbon
Figure 1. Effects of repeated intraarticularadministration of somatostatin (1,000 pg) and triamcinolone acetonide (5 mg) on the course
of antigen-induced experimental arthritis in rabbits.
I
0
1689
2
4
6
8
No. of adnunistration
Figure 2. Second-order polynomial regression of the peak variations of knee joint circumference induced by repeated injection of
somatostatin and triamcinolone acetonide in antigen-induced experimental arthritis, in rabbits.
t-test was used to compare control and placebo groups.
Histopathologic data were analyzed by Wilcoxon rank sum
test; significance levels were computed for each treated
group versus controls. P values less than 0.05 were considered significant.
RESULTS
Joint swelling. The intraarticular injection of
fibrin in fibrin-sensitized rabbits produced a marked
swelling of the knee joint, as measured by its circumference. Swelling peaked within 6 days and then
reached a plateau. In both the control and placebo
groups, the joint swelling persisted to the end of the
experiment, i.e., 86 days after the challenge injection.
No statistically significant differences were found between the placebo and control groups (Student's t-test)
at any time during the experiment.
Treatment with the study drugs started on day
18 post-challenge, when the knee joint swelling was
stable. Animals that received an intraarticular injection of 5 mg triamcinolone acetonide showed a significant reduction of the circumference of the swollen
joint in comparison with placebo-treated animals, with
maximal effect noted at the fifth day post-injection
(Figure 1). Successive administrations of triamcinolone acetonide produced slighter and shorter-lived
effects than the first injection (Figure 1). The differences in mean joint circumference in triamcinolone
acetonidetreated animals compared with placebotreated animals were, however, statistically significant
at all but 2 time points.
Intraarticular administration of somatostatin (at
1690
MATUCCI-CERINIC ET AL
WBC
16000
Controls
14000
Placebo
12000
10000
Triamcinolone
SOM 500 mcglkg
n
SOM 750 mcglkg
SOM 1000 mcglkg
-22
13
PMN
28
55
88
55
88
MN
so1
sol
40
60
30
40
20
20
10
0
0
-22
13
, 82
55
88
-22
13
ESR
28
l2BC
5 :
7 )
i
-22
13
2a
55
88
-22
13
28
55
88
Figure 3. Effects of triamcinolone acetonide and somatostatin (SOM) on hematologic parameters in
rabbits with experimental knee joint arthritis. WBC = white blood cell count; PMN = polymorphonuclear cells; MN = monocytes; ESR = erythrocyte sedimentation rate; RBC = red blood cell count.
500, 750, and 1,000 pg) on day 18 post-challenge
induced dose-related reductions of knee joint circumference. These were particularly significant with so-
matostatin at 1,000 pg (Figure 1). At first injection,
somatostatin reduced knee swelling regardless of
dose; however, this effect was of shorter duration than
SOMATOSTATIN IN EXPERIMENTAL ARTHRITIS
16
12
10
a*
a 2
x=537
0
a
a
0
Som 750
s m loo0
TA
Figure 4. Total score assigned to the histologic sections of rabbit
knee joints removed at the end of the treatment period. Each point
represents the average score for each animal, from 2 independent
observers. The continuous lines with numbers above or below
indicate the mean total scores for each treatment group (see text for
details). Som = somatostatin (500, 750, or 1,000 pg); TA =
triamcinolone acetonide).
that seen with triamcinolone acetonide. When compared with triamcinolone acetonide, all 3 doses of
somatostatin produced, on successive administrations, a reduction of joint circumference similar to the
effect of the first injection; this reduction was always
statistically significant for both the 750 and 1,000 pg
doses and, in several cases, even for the lowest dose
(data not shown). This is shown in Figure 2, where the
peak variations of knee joint circumference induced by
somatostatin and triamcinolone acetonide are plotted
as second-order polynomial regression lines.
No side effects were observed in any of the
treatment groups.
Blood values. The hematologic and hematochemical values of the animals were measured several
times during the experiment (Figure 3). An increased
WBC count was observed in all of the experimental
groups following the induction of arthritis; these
counts subsequently decreased toward normal values
only in animals treated with triamcinolone acetonide.
Increased ESR and slightly decreased albumin:
globulin ratios were also recorded, but there was no
evident effect of treatment on these parameters. No
variations in the RBC counts were observed.
Histologic findings. Histologic examination performed on arthritic knee joints removed from the
animals at the end of the experiment (more than 80
days following induction of arthritis and 65-70 days
after the initiation of pharmacologic treatment) revealed that none of the treatments affected the thick-
1691
ness of synovial lining, compared with that in controls.
All treatment groups, including the placebo group,
showed significant decreases in subsynovial cellularity. Only somatostatin at 750 pg and triamcinolone
acetonide significantly reduced the leukocytic infiltrate, The number of lymphoid follicles was influenced
only by triamcinolone acetonide, while both triamcinolone acetonide and 500 pg somatostatin appeared to
limit vasculitis. Total scores from the global evaluation
of histopathologic parameters are shown in Figure 4.
As expected, triamcinolone acetonide was effective in
reducing the signs of arthritis. Somatostatin at 500 pg
and 750 pg also demonstrated significant results when
compared with controls, whereas somatostatin at
1,000 pg and placebo did not. Necrosis, fibrin deposits, and polynuclear giant cells were not observed in
any group.
DISCUSSION
The animal model of arthritis selected for our
experiments leads to a severe and long-lasting disease
in -60% of the animals and has joint manifestations
similar to those in patients with rheumatoid arthritis.
This study shows that triamcinolone acetonide treatment of the inflamed knee joint results in a significant
and sustained reduction of swelling. The local injection of somatostatin similarly displayed a potent, but
shorter, antiinflammatory effect, the intensity of which
was dose related. For the highest dose tested (1,000
pg), the effect was comparable with that seen with
corticosteroid therapy. Interestingly, while the antiinflammatory activity elicited by successive doses of
triamcinolone acetonide declined both in extent and
duration, the effects of somatostatin remained unchanged at each successive treatment. This may be
one advantage of somatostatin over corticosteroid in
treatment of chronic disease.
The mechanism of action of somatostatin is still
a matter of debate, The effect of somatostatin on
various lymphocyte populations and on leukocyte
migration and activation has been widely studied.
Despite numerous reports documenting the inhibitory
effect of somatostatin on the proliferation of human T
lymphocytes (13) and on neutrophil chemotaxis and
activation induced by SP (7), growth hormone, and
prolactin (28), the role of somatostatin in immunomodulation is still unclear. Somatostatin has been shown to
stimulate polymorphonuclear cell migration in vitro in
a dose-dependent manner (29). Other reports have
shown variable in vitro effects with comparable doses
of somatostatin (
to lo-* moles/liter), including
1692
inhibition of concanavalin A-induced lymphocyte proliferation (13,30), lack of effect on lymph node cells
stimulated with mitogens (31), and enhancement of
untreated (32,33) or mitogen-stimulated lymphocyte
proliferation (34). In our study, somatostatin did not
reduce the number of white blood cells, but it did limit
leukocyte infiltration (mainly lymphocytes) at the
dose of 750 pg and reduced vasculitis (evaluated on
the basis of infiltration in the wall thickness) at the
dose of 500 pg.
The role of somatostatin on synoviocyte proliferation is unclear. The possible presence, in vivo and
in vitro, of somatostatin receptors on rheumatoid
arthritis synoviocytes suggests that this peptide may
directly influence the metabolism of these cells (35). In
the present study, histologic evidence suggests that
neither somatostatin nor triamcinolone acetonide affected synoviocyte proliferation.
The mechanisms by which somatostatin affects
inflammation are complex and yet to be determined,
although neuroendocrine and/or immune effector central mechanisms combined with local actions are probably involved. The antiinflammatory effect of somatostatin may be partly due to its central suppression of
growth hormone release, which has been demonstrated to enhance adjuvant arthritis (36). Somatostatin also inhibits neurogenic inflammation due to negative feedback of terminal afferents with inhibition of
SP release (4) and modulation of cell-mediated immunity (32). Interestingly, somatostatin enhances the
activity of gold salts in psoriatic arthritis (22). Because
gold salts are thought to act through the induction of a
peripheral neuropathy ,the common pathway of somatostatin and gold salts could be the inhibition of SP
release from sensory terminals (37), thus preventing
neurogenic inflammation and reducing nociception.
Endothelial cells might be another target for
somatostatin. The synovial microvascular endothelium may play a central role in the pathogenesis of
rheumatoid arthritis, and a modulation of inflammation
by endothelial cells, through the control of leukocyte
chemotaxis, adhesion, and infiltration, has been suggested (38). In addition, the synovial endothelium has
been directly implicated in the rheumatoid erosive
process because of its ability to generate proinflammatory reactive oxygen species (39,40). Somatostatin
interaction with endothelial cells might induce vasoconstriction and reduce the expression of adhesion
molecules, thus modifying the development of the
immune response by attenuating endothelial cell adhesiveness for mononuclear cells (41).
MATUCCI-CERINIC ET AL
In conclusion, in this experimental model, somatostatin had an antiinflammatory effect that was
almost comparable with that of triamcinolone acetonide in extent, but not in duration. The shorter
duration of the effects of somatostatin compared with
the corticosteroid may be due to the different formulation of the 2 drugs. Triamcinolone acetonide is a
microcrystalline suspension that persists at the site
longer than a soluble preparation such as somatostatin. Because of its rapid in vivo degradation (42),
somatostatin has always been thought to have limited
practical application for clinical use. Although its
antiinflammatory effect when administered by the intraarticular route is shorter than that of triamcinolone
acetonide, it lasts for several days, far longer than its
half-life. This may be related to the protected environment of the articular cavity, the presence of active
metabolites of somatostatin, or a reduction of degrading enzymes at the site of inflammation. Based on
these results, and considering the well-known side
effects of corticosteroid therapy relative to the proven
safety of somatostatin, it seems that somatostatin may
be a valid alternative for intraarticular treatment of
chronic arthritis.
ACKNOWLEDGMENTS
The authors express their gratitude to Prof. Andrzej
Stanisz and Dr. Albert Agro, McMaster University, Hamilton, Canada, for their helpful advice and text revision; to
Ms. A. Fatale for technical assistance, and to Mr. C. Cafiero
for skillful statistical analysis.
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