Localization of Human Glucocorticoid Receptor in Rheumatoid Synovial Tissue of the Knee Joint

7/28/2019 Localization of Human Glucocorticoid Receptor in Rheumatoid Synovial Tissue of the Knee Joint

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Localization of human glucocorticoid receptor in rheumatoid

synovial tissue of the knee joint

CT Tohyama1, M Yamakawa2, A Murasawa1, K Nakazono1, H Ishikawa1

1Department of Orthopaedic Surgery, Rheumatic Centre, Niigata Prefectural Senami Hospital, Niigata, and 2Department of Pathology,Yamagata University School of Medicine, Yamagata, Japan

Objective: This study was conducted to investigate the localization of human glucocorticoid receptors (GCRs) in

the knee synovium of patients with rheumatoid arthritis (RA) and to evaluate the correlation between GCR

expression and the clinical profiles.

Methods: Twenty synovial specimens from RA knees, six from knees with osteoarthritis (OA), and five from

knees with traumatic arthritis (TA) were obtained at surgery. The GCRs were stained immunohistochemically.

The immunopositive cells were counted at random in the lining (synoviocytes) and sublining layers (fibroblastic

and lymphoid cells). The relationship between the GCR-expressing cells and clinical profiles was analysed

statistically.Results: GCRs were expressed in the nuclei of synoviocytes and the fibroblastic and lymphoid cells in the

sublining layer. The GCR-positivity rate of synoviocytes was 67.118.4% in RA, 58.713.5% in OA, and

49.419.7% in TA, differences between the three groups being statistically insignificant. There was a significant

difference in the GCR-positivity rate of sublining fibroblastic cells (p50.029), but not synoviocytes or sublining

lymphoid cells, from RA patients treated with and without prednisolone, while there was no correlation between

the rate for synoviocytes and that for sublining fibroblastic cells from RA patients treated with prednisolone.

Conclusions: GCRs are localized not only on inflammatory lymphoid cells but also on synoviocytes, suggesting

that glucocorticoids could act directly on these cells. Furthermore, the rate of GCR expression on synoviocytes

and sublining lymphoid cells is less suppressed with low-dose prednisolone, regardless of the duration of

treatment.

For many years, glucocorticoids, such as

prednisolone and cortisol, have been used widely

for the treatment of rheumatoid arthritis

(RA) because of their anti-inflammatory and

immunosuppressive effects (13). Although some of

the mechanisms of action of glucocorticoids have

been elucidated, many questions remain (2, 3). In

general, glucocorticoids bind initially to the gluco-

corticoid receptors (GCRs) in the plasma membrane,

and then the GCRligand complex is transferred to

in the nucleus for various genomic actions (4).

Almost all nucleated cells in humans have GCRs,

but glucocorticoids act primarily at sites of inflam-

mation and where the immune response has been

activated (2, 3). In RA patients, GCR activity has

been examined mainly in peripheral mononuclear

lymphocytes, using a binding assay (58). In the main

it has been reported that the expression of GCRs is

downregulated in RA. It is rare to encounter clinical

cases where the steroid effect has been reduced after

long-term glucocorticoid treatment, although the

effect is not the same in each patient due to individual

differences. Joint synovial tissue is ideal for the study

of the pathogenesis of RA, and in particular the

examination of GCR activity, because the main site

of inflammation in this condition is the synovial

tissue itself. To our knowledge, there is little

information available on the immunohistochemical

expression of GCRs in rheumatoid synovial tissue (9,

10). We therefore investigated immunohistochemi-

cally the expression of GCRs in RA synovium on

knee joints to evaluate the correlation between GCR

expression and the patients clinical background.

Materials and methods

Materials

Twenty synovial specimens from 16 RA patients,

six from five patients with osteoarthritis (OA),

C. T. Tohyama, 2-5-13 Minami-machi, Murakami 958-0852,

Niigata, Japan.

E-mail: [email protected]

Received 21 November 2004

Accepted 13 May 2005

426 Scand J Rheumatol 2005;34:426432

# 2005 Taylor & Francis on license from Scandinavian Rheumatology Research Foundation


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and five from five patients with traumatic

arthritis (TA; controls) were obtained at surgery

total knee arthroplasty or arthroscopic surgery at

the Senami RA centre between 1999 and 2000.

The clinical profiles of the patients are

summarized in Table 1. The mean age was 61.7

years (range 3273 years) for the RA patients,

70.7 years (range 6379 years) for the OA

patients, and 56.5 years (range 5156 years) for

the TA patients. The mean disease duration was

16 years (range 135 years) for the RA patients. Of

the 16 RA patients, 12 had been taking prednisolone

at doses ranging from 2.5 to 7.5 mg/day (mean

4.7 mg/day) for 0.111 years (mean 4.3 years).

Some of the RA patients were taking disease-

modifying anti-rheumatic drugs (DMARDs):

four were taking methotrexate, two were taking

either bucillamine or D-penicillamine, and one

was taking cyclophosphamide. The preoperative

rheumatoid factor (RF) was positive in 15 of the

16 RA patients and the C-reactive protein(CRP) level ranged from 0.1 to 18 mg/dl (mean

6.2 mg/dl).

Methods

The synovial tissue specimens were fixed with 10%

formalin immediately after surgery, cut into 5-mm-

thick slices, and embedded in paraffin wax. Four-

micrometre-thick paraffin sections were cut from

these blocks and used for GCR immunostaining. The

GCR was detected by incubation of the sections with

a monoclonal mouse anti-human GCR antibody

(4H2, mouse IgG2a, YLEM, Rome, Italy), and then

visualized using the labelled streptavidinbiotin

peroxidase complex method with the DAKO

LSAB2 system (DAKO, Carpinteria, CA, USA) (11).

The chromogen (in this case horseradish peroxidase)

was visualized with 3,39-diaminobenzidine (Dojin,

Kumamoto, Japan). The immunostained sections

were counterstained with haematoxylin. A mono-

clonal antibody against GCR (4H2) recognized

both GCR-a and GCR-b. The rate of positive

cells in both the lining layer (synoviocytes) and

the sublining layer (fibroblastic and lymphoid cells)

was counted at random in every sample by two

independent examiners (CT and MY) who had

no knowledge of the clinical background of each

sample.

Statistical analysis

The relationship between the rate of GCR-positive

cells and clinical data including age, disease duration,

history of prednisolone treatment, preoperative RF,

and preoperative CRP was analysed statistically with

the Spearmann test or the MannWhitney U-test.

Significance levels were set at pv0.05, and all

statistical analyses were carried out using Statview

for Macintosh.

Table 1. Clinical profiles of rheumatoid arthritis patients.

Case no. Age(years)

Sex Duration ofdisease (years)

Operationprocedure

PreoperativeRF (IU/mL)

PreoperativeCRP (mg/mL)

DMARDs PSL(mg/day)

Duration of PSLtreatment (years)

1 64 Female 20 TKA 64 7.6 DPC 5.0 92 67 Female 16 TKA 146 8.2 BCL 1T 0 03 71 Female 18 TKA 75 1.3 MTX 3 7.5 44 73 Male 1 Arthroscopic 547 18 2.5 0.5

1 Arthroscopic 547 18 2.5 0.55 58 Female 33 TKA 569 1.9 2.0 16 55 Female 10 TKA 163 8.5 CY 2.5 5

10 TKA 163 8.5 CY 2.5 57 50 Female 31 TKA 30 3.1 ACT 3 2.5 5

31 TKA 30 3.1 ACT 3 2.5 58 67 Female 11 TKA 18 6.2 AF 2T 5.0 v1

11 TKA 18 6.2 AF 2T 5.0 v19 68 Female 35 TKA 81 0.1 0 010 67 Male 5 TKA 85 6.8 DPC 5.0 0.8

11 52 Female 26 TKA 1,952 5.1 MTX 2 7.5 1112 32 Female 7 Arthroscopic 112 5.9 GST 0 013 57 Female 16 TKA 102 10.2 MTX 2+DPC 5.0 514 71 Female 8 Arthroscopic 63 3.9 BCL 2 5.0 v115 71 Female 3 TKA 161 0.2 MTX 2 5.0 1.516 66 Male 31 TKA 865 1.5 BCL 1 0 0

RF. rheumatoid factor; CRP, C-reactive protein; DMARDs, disease-modifying anti-rheumatic drugs; PSL, prednisolone; TKA, total kneearthroplasty; DPC, D-penicillamine; BCL, bucillamine; MTX, methotrexate; CY, cyclophosphamide; ACT, actarid; AF, auranofin; GST, goldsodium thiomalate.

Glucocorticoid receptor in RA synovium 427


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Results

GCRs were expressed on the nuclei of cells in all of

the samples. The mean percentage (standard

deviation) of GCR-positive lining synoviocytes per

randomly counted synoviocytes was 67.118.4% in

the RA group, 58.713.5% in the OA group, and

49.419.7% in the TA group (Figure 1). Although

many cases of the group exhibited high percentages

of GCR-positive cells, there was no significant

difference among the three groups (RA vs. OA:

p50.287, RA vs. TA: p50.118, OA vs. TA: p50.584by the MannWhitney U-test). GCRs were detected

predominantly on the inflammatory lymphoid cells in

the sublining layer (Figure 2A, B). The fibroblastic

cells in the sublining layer were occasionally GCR-

positive (789%; Figure 2B) in all RA cases.

Compared with the OA and TA patients (Figure 3),

most of the RA patients had a high percentage of

GCR-positive cells in this layer, although again the

differences were not significant among the three

groups (RA vs. OA: p50.394, RA vs. TA: p50.154,

OA vs. TA: p50.361 by the MannWhitney U-test).

In the sublining layer, GCRs were detected in themajority of lymphoid cells. The other cell types of

the sublining cells, such as vascular endothelial cells

and smooth muscle cells, and macrophages were also

positive for GCRs.

Evaluation of intraobserver reproducibility revealed

no statistically significant difference, and a strong

correlation was found between the two observers. In

the RA patients who had been taking the low doses of

prednisolone, the rate of GCR-positive fibroblastic

cells per randomly counted sublining fibroblastic cells

was significantly higher than in those who had not

received prednisolone treatment (Figure 5, p5

0.029).

There was no significant difference in the rate of GCR-

expressing synoviocytes and sublining lymphoid cells

between RA cases with and without prednisolone

treatment (Figure 4, 6).

Figure 1. Comparison of the frequency of glucocorticoid receptor

(GCR)-positive synoviocytes among rheumatoid arthritis, osteoar-

thritis, and traumatic arthritis.

A

B

Figure 2. Immunostaining of glucocorticoid receptors (GCRs) in

synovial tissue obtained from a female patient (67 years old) with

rheumatoid arthritis (RA). (A, B) Most of the massively infiltrating

lymphoid cells in the sublining layer express GCRs. Note the

frequent positive reaction on synoviocytes, located between the

arrows. (C) Occasional fibroblastic cells (arrows) in the sublining

layer express GCRs. This section was counterstained with

haematoxylin. Original magnification (A, B)6

200.

428 CT Tohyama et al


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Finally, the correlation between the rate of GCR-

positive cells and other clinical characteristics of RA

cells and other clinical patients including their cells

and other clinical age, duration of the disease,

duration of prednisolone treatment, and preoperative

RF and CRP levels was examined (Table 2). The

level of RF correlated well, but not significantly, with

the rate of GCR-positive synoviocytes (r50.473,

p50.064) and sublining lymphoid cells (r50.036,

p50.084). The preoperative CRP level was signifi-

cantly correlated with the rate of GCR-positivesublining lymphoid cells (r50.414, p50.046).

Discussion

A reduction in GCR activity has been demonstrated

in a variety of cells in RA synovial tissues

after corticosteroid treatment, and this is one of the

candidate causes of steroid resistance in therapy (12

18). In most of these studies a binding assay with 3H-

dexamethasone was applied to evaluate GCR activity

quantitatively (68, 15). The present study is the first

to examine quantitatively the immunohistochemical

expression of GCR on cells in synovial tissues takenfrom patients with active RA.

A B

Figure 3. Immunostaining of GCRs in synovial tissue obtained from a male patient (51 years old) with traumatic arthritis (A) and from a

female patient (71 years old) with osteoarthritis (B). Vascular endothelial cells and smooth muscle cells are evidently positive. Note the GCR

expression on lining synoviocytes even in non-RA synovial tissues. This section was counterstained with haematoxylin. Original

magnification (A, B) 6200.


(GCR)-positive synoviocytes between RA groups treated with and

without prednisolone.


(GCR)-positive sublining fibroblastic cells between RA groups

treated with and without prednisolone.



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It is well known that almost all nucleated cells

in humans have GCRs (2, 3), and that GCR activity

is found mainly in lymphoid cells (58). In the

study presented here, GCRs were indeed found

on many types of cell, such as lymphoid cells,

fibroblastic cells, endothelial cells, and smooth

muscle cells in the sublining layer. In addition, we

found that most of the lining synoviocytes expressed

GCRs (67.118.4% in the RA group, 58.713.5%

in the OA group, and 49.419.7% in the TA group),suggesting that glucocorticoids directly target syno-

viocytes. As glucocorticoids can induce a G1 cell-

cycle arrest and programmed cell death, they exert an

antiproliferative response in different cell types,

including fibroblasts (10). The previous reports also

support the possibility of glucocorticoids acting

directly on synoviocytes (19, 20).

Several studies have recently reported GCR

isoforms, such as a, b, and c, and also mutations

and/or polymorphisms of the GCR gene (2126).

In particular, GCR-b function was reported as a

dominant-negative inhibitor GCR-a. However,

conflicting data have also been reported (27). One

paper states that the ratio GCR-b/GCR-a is very

low (1/104) (28), although there might be

some difference between the tissues and cells (29).

We have indeed experienced steroid-resistant RA

cases clinically, but only a very few such cases.

Additionally, the previous reports were mostly

based on the molecular level, while more factors

might have affected each other in vitro. Therefore,

our data showed general GCR localization in

synovium clinically with some variation for each

patient, which is the same pattern as OA and

traumatic cases.

Although the GCRs were detected on the

lining synoviocytes and sublining fibroblastic

and lymphoid cells, regardless of prednisoloneadministration, the rate of GCR expression on

subsynovial fibroblastic cells in RA cases

pretreated with prednisolone was significantly

lower than in those who had not received

prednisolone treatment. In our cases the maximum

glucocorticoid dose was 7.5 mg/day, and our

data have demonstrated that a low-dose glucocorti-

coid treatment (30) does not downregulate GCR

expression on synoviocytes and extensively infiltrat-

ing lymphoid cells, even after long-term usage. This

concurs with the finding of previous reports that low-

dose steroid treatment may not suppress GCRactivity (16, 31). Our data provide clinical support

for the fact that GCR activity at the onset of RA

without steroid therapy could be higher, because

higher GCR activity was detected in most RA cases

regardless of whether there were other factors present

that could suppress GCR activity in the lengthy

duration of the disease (32).


(GCR)-positive sublining lymphoid cells between RA groupstreated with and without prednisolone.

Table 2. Correlation between the rate of glucocorticoid receptor-positive cells and clinical profiles of rheumatoid arthritis patients.

Clinical profiles Synoviocytes

Sublining layer

Fibroblast ic cel ls Lymphoid cells

Age r 0.103 0.119 0.103p 0.403 0.748 0.938

Duration ofdisease

r 0.108 0.072 0.239p 0.794 0.430 0.447

Duration ofprednisolonetreatment

r 0.093 0.379 0.039p 0.808 0.139 0.694

Rheumatoidfactor

r 0.473 0.503 0.036p 0.064 0.338 0.084

C-reactiveprotein

r 0.154 0.205 0.414p 0.699 0.691 0.046*

r5

correlation coefficient, p5

p-value. *pv

0.05.



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Preoperative CRP levels were significantly corre-

lated with the rate of GCR-positive fibroblastic cells

in the sublining layer. This supports the idea that an

increased rate of GCR-positive fibroblastic cells may

be related to the pathogenesis of RA, as has been

reported previously (15, 31).

Some inflammatory stimuli may lead to the induc-

tion of proinflammatory cytokines such as tumour

necrosis factor-a and interleukins-1, -6, and -8 (33).

These cytokines activate transcription nuclear factor-

kB (NF-kB), which can then enhance GCR expression

in the cytoplasm and translocate into the nucleus (34).

Furthermore, the induction of endogenous glucocor-

ticoids by proinflammatory cytokines will activate

GCRs in the nucleus, which can then repress NF-kB

expression. These mechanisms lead to the anti-inflam-

matory effect of glucocorticoids (10, 12, 3537).

Glucocorticoids are known to play an important

role in various physiological functions, not only by

modulatinginflammationbut also by inhibiting,among

other things, growth (37), and osteoporosis (1). Thelong-term administration of glucocorticoids also

results in many adverse side-effects (1). Thus,

improvements in the treatment of RA will be made

if non-glucocorticoid compounds can be developed

that activate GCRs or induce directly the expression

of NF-kB (32, 38).

We have demonstrated here the localization of

GCRs not only on inflammatory lymphoid cells but

also on synoviocytes, suggesting that corticosteroids

could act directly on these cells. It was also revealed

that the rate of GCR expression on synoviocytes and

extensively infiltrating lymphoid cells was less sup-pressed with low-dose prednisolone treatment,

despite long-term use.

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Localization of Human Glucocorticoid Receptor in Rheumatoid Synovial Tissue of the Knee Joint

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