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Changes as a Result of Reversal to Euthyroidism

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Chinese Journal of Physiology 46(4): 181-186, 2003
181
Osteoporotic Cytokines and Bone Metabolism
on Rats with Induced Hyperthyroidism;
Changes as a Result of Reversal to
Euthyroidism
Gönül Simsek 1, Yesari Karter 2, Seval Aydın 3, and Hafize Uzun 3
1
⋅
I stanbul University
Cerrahpa S a Faculty of Medicine Department of Physiology
2 ⋅
I stanbul University
Cerrahpa S a Faculty of Medicine Department of Internal Medicine
3 ⋅
I stanbul University
Cerrahpa S a Faculty of Medicine Department of Biochemistry
Istanbul, Turkey
Abstract
Hyperthyroidism is characterized by increased bone turnover and resorptive activity. Raised
β , IL-6 and tumor necrosis factor
levels of serum osteoporotic cytokines, such as interleukin (IL) -1β
α
(TNF)-α have been demonstrated previously in hyperthyroidism. These elevations are controversial and
it is difficult to differentiate the contribution of thyroid hormones to the elevation of cytokines from that
of the autoimmune inflammation in Graves’ disease (GD) and follicular cell damage in thyroiditis.
β , IL-6, TNF-α
α levels and bone
Therefore, we investigated the effect of thyroid hormones on serum IL-1β
metabolism on L-thyroxine induced hyperthyroid rats and changes in cytokine levels and bone metabolism
on the same rats after reversal to euthyroidism. Rats were treated with L-thyroxine for 5 weeks (0.4 mg/
β , IL-6, TNFα
α , Calcium (Ca), phosphorous (P),
100 g food). Plasma T 3 , T 4 , TSH and serum IL-1β
parathyroid hormone (PTH), alkaline phosphatase (ALP), bone alkaline phosphatase (B-ALP) levels
were measured and differential leucocyte counts were made initially, at the 5th week of the experiment
(hyperthyroid state) and 5 weeks after quitting the administration of L-thyroxine (euthyroid state).
β , IL-6 and TNFα
α were noted in hyperthyroidism (P<0.001). In euthyroid
Significant rises in serum IL-1β
β , IL-6 and TNFα
α decreased significantly, but IL-β
β and TNFα
α were significantly higher than
state, IL-1β
the baseline values (P<0.05) while IL-6 levels turned back to the baseline values. Plasma T3 and T 4 levels
were significantly correlated with serum cytokines in hyperthyroid state while there was no correlation
in euthyroid states. Ca and P levels did not differ significantly while PTH levels declined significantly
in the hyperthyroid state (P<0.05). After the reversal to the euthyroidism, there was no significant
change in Ca, P and PTH levels. ALP and B-ALP increased significantly in hyperthyroidism (P<
0.001, P<0.01) and they did not decrease in euthyroid state. The lymphocyte number and ratio in
differentials increased significantly in the hyperthyroid state (P<0.001). In euthyroidism they decreased
significantly (P<0.001) but it was significantly higher than the baseline value (P<0.05). Our findings
showed that the deleterious effect on bone metabolism in hyperthyroidism might be mediated by
cytokines and the increased bone turnover in hyperthyroidism failed to decrease despite euthyroidism.
β , interleukin 6, tumor necrosis factor-α
α,
Key Words: hyperthyroidism, interleukin-1β
bone metabolism, bone turnover
Corresponding author: Dr.Gönül Sim S ek, 1.Ulus Mah. Portakal YokuS u Sok. Gürcü Kızı Cıkmazı.
Sayhan Sitesi C Blok, B GiriSi, D:10 34100
,
⋅
Be S ikta S /I STANBUL/TURKEY. Tel: 90-212-4143071; Fax: 90-212-4143072; e-mail: gdincsimsek@yahoo.com
Received: April 5, 2003; Revised: August 10, 2003; Accepted: August 22, 2003.
182
SIMSEK, KARTER, AYDIN AND UZUN
Introduction
Thyroid hormones are necessary for normal
skeletal growth. However, their excess may lead to
bone resorption. Ultimately hyperthyroidism is
accompained by osteoporosis (24, 34). Although
there is ample evidence for increased bone turnover
in hyperthyroidism (10), the precise mechanisms for
this action of thyroid hormone on bone remain unclear.
Locally produced factors are important in
maintaining normal bone metabolism (19). IL-6 in
particular, has a major influence on bone turnover and
stimulates differentiation and proliferation of
osteoclasts (16). IL-1β and TNFα are also implicated
in bone resorption, particularly in high turnover states
(25). Raised levels of serum osteoporotic cytokines
such as IL-1β, IL-6 and TNFα have been reported in
hyperthyroidism with different etiologies like Graves’
disease (GD), toxic nodular goiter (TNG) and subacute
thyroiditis (4, 7, 17). Conversely there exists studies
reporting that IL-1β and TNFα have failed to rise in
GD and TNG (28, 29). Similarly, in the postpartum
thyroiditis (1) and interferon-γ thyroiditis, IL-6 (20)
failed to increase.
Serum IL-6 has a number of sources, including
blood mononuclear cells and bone tissue. IL-6 mRNA
is also present in thyroid follicles (13). In thyroid
hyperfunction like TNG, intrathyroidal production of
IL-6 is one source of elevated IL-6 levels in serum
(17). In GD although follicular cells are also able to
express certain cytokines, intrathyroidal lymphocytes
are the main source of IL-6 production (36). Serum
IL-6 normalizes on remission of the subacute
thyroiditis, indicating that it is related to follicular
cell damage (17). The data about the levels of
cytokines in hyperthyroidism are controversial and it
has remained difficult to differentiate the contribution
of thyroid hormones to these elevations from that of
the autoimmune inflammatory process in GD,
hyperfunction of the gland in TNG and follicular cell
damage in thyroiditis. To address this question, we
investigated the effects of thyroid hormones on serum
IL-1β, IL-6 and TNFα levels and on bone metabolism
on L-thyroxine-induced hyperthyroid rats
intraindividually. As discrepancy exist in the results
of studies to determine whether euthyroidism after
medical therapy can completely normalize bone
metabolism (18, 23), the changes in cytokines and
bone metabolism were also investigated on the same
rats that were taken back to euthyroidism.
Materials and Methods
Experimental Design
Fifteen female adult Wistar Albino rats of 250-
300 g body weight were supplied from the Laboratory
Animal Service of the University of Istanbul. The
animals were permitted ad libitum access to standard
laboratory chow and tap water. Hyperthyroidism was
induced by administration of L-thyroxine (Organon
Inc, Istanbul, Turkey) 0.4 mg/100 g food for 5 weeks
(15, 30, 31, 35).
Blood samples were taken from tail vein initially,
5 weeks after the administration of L-thyroxine
(hyperthyroid state) and 5 weeks after quitting Lthyroxine administration (euthyroid state).
Biochemical Measurements
The plasma T 3,T 4,TSH and serum IL-1β, IL-6
and TNFα calcium (Ca), phosphorous (P), Parathyroid
hormone (PTH), alkaline phosphatase (ALP) and bone
alkaline phosphatase (B-ALP) were analyzed.
Additionally differential leucocyte counts were made.
T 3 , T 4 and TSH analyses were performed by
chemiluminescent enzyme immunoassay (Diagnostic
Products Corporation, Los Angeles, CA, USA). IL1β, IL-6 and TNFα were measured by ELISA
(Quantikine, R&D Systems, Minneapolis, MN, USA).
The sensitivity for IL-1β, IL-6 and TNFα were 5, 10,
5 pg/mL respectively. Ca, P were measured by
autoanalyser (Hitachi 717, Boehringer Mannheim,
Germany). PTH was analysed by immuno radiometric
assay (Diagnostic Systems Laboratories. Inc., Texac,
USA). ALP and B-ALP were determined by a kineticenzymatic method (Boehringer, Mannheim,
Germany). For differential leucocyte counts, blood
smears were stained with May-Grunwald and Giemsa
Solutions (Merc, Darmstad, Germany). At the same
time the total leucocyte number and the total numbers
of subgroubs in mm3 were determined by hematology
analyzer (Beckman Coulter, HMX, USA).
Statistical Analysis
Data were expressed as mean(SD) and analyzed
by repeated measures of ANOVA. For adjustment of
multiple comparisons Least Significant Difference
(LSD) was used. Correlations between plasma T3/T4
and serum cytokines in different stages were tested by
Pearson-Bravis test and P less than 0.05 was accepted
as significant.
Results
After 5 weeks of L-thyroxine administration the
measured values of significantly increased T3, T4 and
significantly decreased TSH served to confirm the
establishment of hyperthyroidism in the rats. Five
weeks after quitting L-thyroxine administration, T 3,
T 4 and TSH values reversed to the baseline values
CYTOKINES IN HYPERTHYROIDISM; REVERSAL TO EUTHYROIDISM
(Table 1).
Significant rises in serum IL-1β, IL-6 and TNFα
were noted in hyperthyroidism (P<0.001). In
euthyroid state IL-1β and TNFα decreased (P<0.01),
but they did not arrive at the baseline values and they
were significantly higher than the baseline values (P
<0.05). Meanwhile IL-6 levels reversed to the baseline
values (Table 2). Plasma T 3 and T 4 levels were
significantly correlated with serum cytokines (IL-1β
r=0.59, P<0.01 and r=0.69, P<0.01; IL-6 r=0.75,
P<0.01 and r=0.67, P<0.01; TNFα r=0.64, P<0.05
and r=0.54, P<0.05 respectively) in hyperthyroid state
(Fig. 1). However T 3 and T 4 levels did not correlate
with serum cytokines in euthyroid states.
Serum Ca and P levels did not differ significantly
compared to baseline values whereas PTH levels
declined significantly in the hyperthyroid state (P<
0.05). After reversal to the euthyroidism there was no
significant change in Ca, P and PTH levels (Table 2).
ALP and B-ALP increased significantly in
hyperthyroidism compared to baseline values (P<
0.001 and P<0.01 respectively) and they did not
decrease in euthyroid state (Table 2).
The lymphocyte number in differentials
increased significantly from 7400±788/mm 3 (61.0±
2.94%) to 9893±775/mm 3 (80.4±3.97%) in the
hyperthyroid state (P<0.001). In euthyroidism the
number of the lymphocyte decreased significantly to
8211±1517/mm3 (70.8±4.73%) (P<0.001), but it was
significantly higher than the baseline values (P<
0.05).
Discussion
In our study, the levels of cytokines increased
due to administration of L-thyroxine. Plasma T 3 and
T 4 levels were significantly correlated with serum
cytokines in hyperthyroid state. The increases in the
level of IL-6 were explained with autoimmune
inflammation, thyroid hyperfunction and follicular
cell damage in the hyperthyroid patients with different
etiology like GD, TNG, and thyroiditis (17, 21).
Watson et al. (36) reported that intrathyroidal
lymphocytes were the main source of IL-6 production
in GD although follicular cells were also able to
express certain cytokines. As the thyroid hormones
were administrated externally and there were
correlations between plasma T 3 /T 4 and serum
cytokines in hyperthyroid state the origin of elevated
levels of IL-1β, IL-6 and TNF-α were due to thyroid
hormones in our study and we showed that
osteoporotic cytokine levels increased in the
circulation in hyperthyroidism independent of the
etiology.
Osteoblasts and blood mononuclear cells express
thyroid hormone receptors (5, 6, 26). For this reason
183
Table 1. The plasma levels of T3 , T4 and TSH in
baseline, hyperthyroid and euthyroid state
of rats (means±SD; n=15)
State
T3 (ng/dL)
T4 (µg/dL) TSH (µIU/mL)
Baseline
75.45±7.18 4.66±1.25
Hyperthyroid 178.91±7.68 12.32±3.23
Euthyroid
71.81±5.87 4.59±1.09
Pa
<0.001
<0.001
Pb
<0.001
<0.001
Pc
NS
NS
2.24±0.44
1.94±0.21
2.26±0.43
<0.01
<0.01
NS
Pa, difference of hyperthyroid state from baseline; Pb,
difference of euthyroid state from hyperthyroid state; Pc,
difference of euthyroid state from baseline; NS, not significant
in hyperthyroidism the secretion of osteoporotic
cytokines from the osteoblast and/or blood
mononuclear cells may increase by the effect of
increased amount of thyroid hormones.
Hyperthyroidism is a well documented cause of
impaired bone turnover characterized by increased
osteoblastic and osteoclastic activity, resulting in
predominance of bone resorption and in decreased
bone mass (5, 24). There is no knowledge on the
direct stimulating effects of thyroid hormones on
osteoclastic activity. Besides stimulating stromal
cell progenitors, these hormones are reported to have
important functions in osteoblastic maturation (8).
Therefore, the cytokine secretion from stromal cells
and osteoblasts may increase by the effect of increased
thyroid hormones in hyperthyroidism.
IL-6 is produced by both stromal cells and
osteoblastic cells in response to stimulation by the
bone-resorbing cytokines IL-1 and TNF (11, 22). IL6 stimulates bone resorption by enhancing osteoclast
proliferation and differentiation (16). In vitro thyroid
hormones do not stimulate IL-6 production directly in
fetal rat limb bones (33). However in the presence of
physiological concentrations of thyroid hormones,
the IL-1 stimulated IL-6 response and bone resorption
is greatly increased in fetal rat limb bone cultures
(33). In our study it was seen that the levels of IL-1β,
IL-6 and TNFα increased in the hyperthyroid state.
After the reversal of the rats to euthyroidism, we saw
that the level of IL-6 arrived at the baseline values
while the levels of IL-1β and TNFα decreased
significantly, but not to the baseline values (Table 2).
This may suggest the stimulation of IL-6 by IL-1 at
certain concentrations. As the concentration of IL-1
decreases to the values below these concentrations, it
will not stimulate IL-6 any more.
Blood mononuclear cells produce IL-6 under
normal basal conditions (11). Lakatos et al. (17)
184
SIMSEK, KARTER, AYDIN AND UZUN
Table 2. Serum levels of measured parameters in baseline, hyperthyroid and euthyroid states of rats
(means ± SD; n=15)
Parameter
IL-1β (pg/mL)
IL-6 (pg/mL)
TNFα (pg/mL)
Ca (mg/dL)
P (mg/dL)
PTH (mg/dL)
ALP (U/L)
B-ALP (U/L)
Baseline
Hyperthyroid
Euthyroid
Pa
Pb
Pc
807.08±46.87
1007.50±69.16
510.00±29.07
9.19±0.85
7.45±0.87
2.91±0.39
189.75±39.18
27.50±4.48
967.50±40.92
1111.91±67.34
559.16±30.80
9.46±0.98
7.70±0.66
2.73±0.37
219.0±42.16
37.25±8.41
860.58±81.23
1001.66±75.17
525.41±31.43
9.20±0.90
7.62±0.66
2.80±0.37
217.50±42.24
36.91±8.40
<0.001
<0.001
<0.001
NS
NS
<0.05
<0.001
<0.01
<0.01
<0.001
<0.01
NS
NS
NS
NS
NS
<0.05
NS
<0.05
NS
NS
NS
<0.001
<0.01
Pa, difference of hyperthyroid state from baseline; Pb, difference of euthyroid state from hyperthyroid state; Pc, difference
of euthyroid state from baseline; NS, not significant
Fig. 1. The correlations between the levels of plasma T3/T4 and serum cytokines in hyperthyroid state. *P<0.05, **P<0.01
showed the increasing of basal IL-6 secretion from
mononuclear cells in GD and TNG. Horowitz et al.
(14) reported that IL-1β and TNFα secreted from
peripheral monocytes induced the secretion of IL-6
by stimulating stromal cells and osteoblast. In our
study lymphocytosis was observed in hyperthyroid
rats while there was no change in monocyte number
and ratio. We also showed lymphocytosis in
hyperthyroidism in our previous study (31). IL-1β is
also secreted from lymphocytes (9). Increased
numbers of lymphocytes encountered in
hyperthyroidism may be responsible for high IL-1β
levels. This may lead to elevated IL-6 levels released
from activated osteoblasts. After the reversal of the
rats to euthyroidism the number of lymphocyte
decreased significantly, but it was noticable that these
values were significantly greater than the baseline
values.
Barnefalk et al. (3) found out that high plasma
Ca concentration increased the secretion of IL-6 from
mononuclear blood cells, but in our study hyperthyroid
rats showed no significant increase in serum Ca levels
while there were significant increases in IL-1β, IL-6
and TNFα levels. We also demonstrated that thyroid
hormones did not cause significant changes in the
plasma level of Ca in our previous studies (30, 31,
32).
Thyroid hormones given in supraphysiological
doses result in a reduction in net bone tissue mass by
an accentuation in remodelling, causing increased
resorptive activity (2). Enhanced bone destruction
results in a slight rise in serum Ca, which in turn
causes a compensatory reduction in the PTH level and
augmentation of renal P retention (27). Our findings
of insignificant increases in serum Ca and P levels
and a significant decline in PTH are consistent with
these data. Reversal to euthyroidism did not cause
any change in Ca, P and PTH levels (Table 2).
CYTOKINES IN HYPERTHYROIDISM; REVERSAL TO EUTHYROIDISM
The levels of serum ALP and B-ALP were found
to increase significantly in hyperthyroidism in our
study. These findings are consistent with the activation
of the osteoblasts in cohort with the increasing of
osteoclastic activity. However, we did not observe
any significant decrease in ALP and B-ALP levels
after reversal to euthyroidism (Table 2). Garnero et
al. (10) concluded that B-ALP is an important
biochemical marker demonstrating the increase in
bone turnover. Our findings showed that increased
bone turnover in hyperthyroidism failed to decrease
despite euthyroidism.
The deleterious effects on bone tissue in
hyperthyroidism may be mediated by IL-1β, IL-6 and
TNFα. Despite the high bone turnover, the reversal
of IL-6 to the baseline values suggests that IL-6, may
not a sensitive indicator for high bone turnover. It
will be important to investigate for the mechanism
responsible for the ongoing high bone turnover despite
euthyroidism.
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