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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 1 78-81
Copyright © 1997 by The Endocrine Society

Clinical Studies

Serum Interleukin-6 and Bone Metabolism in Patients with Thyroid Function Disorders1

Peter Lakatos, Janos Foldes, Csaba Horvath, Laszlo Kiss, Agnes Tatrai, Istvan Takacs, Gabor Tarjan2 and Paula H. Stern

1st Department of Medicine (P.L., J.F., C.H., A.T.,I.T.), Semmelweis University Medical School, Budapest, Hungary, H-1083; Hetenyi Geza County Hospital (L.K.), Szolnok, Hungary, H-5000; and Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Medical School (P.L., G.T., P.H.S.) Chicago, Illinois 60611

Address all correspondence and requests for reprints to: Peter Lakatos, 1st Department of Medicine, Semmelweis University Medical School, Koranyi 2/A, Budapest, H-1083, Hungary.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
To determine the possible involvement of interleukin-6 (IL-6) in the bone loss of hyperthyroidism, relationships between thyroid status, biochemical and densitometric parameters of bone metabolism, and IL-6 were studied in female subjects. Patients with hyperthyroidism caused by either toxic nodular goiter or Graves’ disease had significantly higher serum IL-6 concentrations than normal controls. Within the control group, serum IL-6 was higher in postmenopausal than in premenopausal women, but this influence of menopausal status was not seen in the hyperthyroid patients. The production of IL-6 by blood mononuclear cells was higher in cells from the hyperthyroid women. Bone turnover was increased in the hyperthyroid patients based on serum osteocalcin and urinary deoxypyridinoline excretion, and the hyperthyroid group also had reduced radius bone mineral content (BMC). A subgroup of hyperthyroid patients who had the lowest BMC (values more than 1 SD below normal age-matched controls) also had serum IL-6 concentrations significantly greater than those of hyperthyroid patients showing less reduction of BMC. The correlations observed in this study support the possibility that IL-6 plays a role in mediating the bone loss that results from excess thyroid hormone.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THYROID hormones are necessary for normal skeletal growth. However, their excess may result in bone loss, especially in adulthood. Hyperthyroidism is accompanied by osteoporosis (1) and increased fracture rate (2). Although there is ample evidence for increased bone turnover in hyperthyroidism (3, 4, 5, 6), the exact mechanism of the deleterious effect of thyroid hormones has not yet been elucidated.

Locally produced factors are important in maintaining normal bone metabolism (7). Interleukin-6 (IL-6), particularly, has a major influence on bone turnover. IL-6 stimulates differentiation and proliferation of osteoclasts (8), thus leading to increased bone resorption (9, 10, 11). Increased serum IL-6 level has been reported in several pathological states. Among these, multiple myeloma (12) are characterized by excessive osteoclast development and bone loss.

IL-6 is produced in a variety of tissues, such as bone (13), the thyroid (14), and blood mononuclear cells (15). These mononuclear cells also express thyroid hormone receptors (22). The effect of thyroid hormones on serum IL-6 and its relation to thyroid hormone-stimulated bone loss have not been elucidated. To address this question, we studied serum IL-6 levels, IL-6 production by blood mononuclear cells, and bone metabolism in patients with thyroid disorders.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

The study population consisted of 42 hyperthyroid (age: 24–66 yr; 23 pre- and 19 postmenopausal) and 19 hypothyroid (age: 28–64 yr; 9 pre- and 10 postmenopausal) Caucasian women before antithyroid or replacement therapy, respectively, as well as 30 healthy euthyroid controls (age: 22–65 yr; 15 pre- and 15 postmenopausal). The hyperthyroid group included 22 patients with toxic nodular goiter (TNG) (age: 34–66 yr) and 20 patients with Graves’ disease (GD) (age: 24–47 yr). Hypothyroidism was caused by autoimmune thyroiditis in 10 patients, radioisotope treatment in 5 patients and surgery in 4 patients. Subjects in all groups were free of any diseases or were not taking any medication known to affect calcium metabolism. Informed consent was obtained from all subjects.

Mononuclear cell cultures

Blood mononuclear cell cultures were prepared as described by Pacifici et al. (16). Briefly, mononuclear cells separated on Ficoll/Hypaque were resuspended in medium at a concentration of 106 cells/mL and 1-mL aliquots were placed in a 24-well tissue culture plate for 2 h at 37 C, in a humidified atmosphere containing 5% CO2/95% air. The adherent cells were then incubated for 48 h in 1 mL DMEM (Sigma Chemical Co., St. Louis, MO) supplemented with 5% heat-inactivated FBS ± 1 µg/mL phytohemagglutinin (PHA) (Sigma Chemical Co.). Supernatants from quadruplicate cultures were stored at -20 C until assayed.

Biochemical measurements

Blood was drawn after an overnight fast, centrifuged, and serum was stored at -20 C until determination. IL-6 was assayed from sera and mononuclear cell culture supernatants by ELISA (Quantikine, R&D Systems, Minneapolis, MN). The sensitivity of the method was 0.7 pg/mL. When assaying mononuclear cell culture supernatants, results were expressed as picograms per 106 adherent cells. Serum osteocalcin (OC) was measured by NovoCalcin ELISA (Metra Biosytems, Mountain View, CA), sensitivity was 0.45 ng/mL. Urinary free deoxypyridinoline cross-link excretion (DPD) was measured by ELISA (Pyrilinks-D; Metra Biosystems) from the first morning void with a sensitivity of 3 nM. Final results were expressed as DPD nM/creatinine mM.

Bone densitometry

Bone mineral content (BMC) was measured at the lumbar spine and femoral neck by dual-enengy x-ray absorptiometry (Norland XR-26; Norland, Fort Atkinson, WI) and at the radius midshaft by single-photon absorptiometry (NK-364; Gamma Ltd., Budapest, Hungary).

Statistical analysis

Data were expressed as mean ± SEM and analyzed by two-tailed Students’s t test and one-way ANOVA, as appropriate. Subsequent mean comparison tests were performed by Tukey’s significant difference test.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Serum IL-6 values (Fig. 1Go) were significantly increased in the hyperthyroid group compared with the controls (18.2 ± 0.8 vs. 6.2 ± 1.3 pg/mL; P < 0.01). No difference was found between TNG and GD patients. IL-6 concentrations of hypothyroid patients (5.3 ± 2.0 pg/mL) did not differ statistically from control subjects. There was no correlation between individual IL-6 concentrations and thyroid hormone levels in either group. When the values from the pre- and postmenopausal women were compared (Fig. 2Go), significantly higher serum IL-6 was found in healthy postmenopausal controls (2.3 ± 0.7 vs. 10.1 ± 0.9 pg/mL; P < 0.01) but not in postmenopausal patients with hyperthyroidism [17.4 ± 0.9 vs. 18.6 ± 1.0 pg/mL; not significant (NS)] or hypothyroidism (5.2 ± 0.9 vs. 5.4 ± 1.1 pg/mL; NS).



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  		Figure 1. Serum IL-6 in thyroid disorders. Data represents mean ± SEM. **, P < 0.01 vs. control. Hyper, Hyperthyroidism; hypo, hypothyroidism.

 


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  		Figure 2. Serum IL-6 in thyroid disorders: effect of menopause. Data represents mean ± SEM. **, P < 0.01 vs. premenopausal controls; ++, P < 0.01 vs. postmenopausal controls. Solid bars, Premenopausal; hatched bars, postmenopausal.

 
BMC (Table 1Go) was reduced significantly only at the radius midshaft of the hyperthyroid patients. There was no difference in BMC between TNG and GD subjects (0.70 ± 0.03 vs. 0.68 ± 0.04 g/cm; NS). BMC of the hypothyroid group was not different from controls. Serum IL-6 values did not correlate with BMC in either group. However, serum IL-6 of those patients with hyperthyroidism whose BMC was lower than -1 SD below the normal age-matched population values (17) was significantly higher than of those whose BMC was above that threshold (23.8 ± 1.1 vs. 16.8 ± 0.7; P < 0.05; Fig. 3Go).


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  		Table 1. BMC in thyroid function disorders

 


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  		Figure 3. Serum IL-6 and radius BMC. Data represents mean ± SEM. -1.0 SD means that BMC is below the age-matched normal population values by 1 SD.

 
Basal IL-6 production of blood mononuclear cells in hyperthyroid women, either with TNG and GD, was higher than in controls (367 ± 132 and 413 ± 112 pg/106 cells, respectively, vs. 158 ± 87 pg/106 cells; P < 0.05; Fig. 4Go). There was no significant difference between the TNG and GD groups. In response to PHA, controls and GD patients showed a significant increase in IL-6 production (802 ± 176 and 846 ± 181 pg/106 cells; P < 0.05 vs. no PHA of respective group; Fig. 4Go), whereas TNG patients did not exhibit a further enhancement (391 ± 155 pg/106 cells). The basal IL-6 production by mononuclear cells in hypothyroid subjects (139 ± 63 pg/106 cells) was not statistically different from controls and it could not be stimulated with PHA (161 ± 79 pg/106 cells).



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  		Figure 4. IL-6 production of blood mononuclear cells in hyperthyroid women. Data represent mean ± SEM. Solid bars, -PHA; hatched bars, +PHA. *, P < 0.05 vs. -PHA control; +, P < 0.05 vs.-PHA of respective group.

 
Serum OC values of the hyperthyroid group was significantly higher than that of controls (19.6 ± 1.6 vs. 5.5 ± 0.4 ng/mL; P < 0.01; Table 2Go). Urinary DPD excretion of these patients was also increased (15.8 ± 1.1 vs. 6.1 ± 0.7 nM/mM creatinine; P < 0.01; Table 2Go). However, subjects with BMC below -1 SD of age-matched normal population values had higher OC (24.9 ± 0.7 vs. 16.8 ± 0.9 ng/mL; P < 0.05) and DPD (18.3 ± 1.0 vs. 13.1 ± 0.6 nM/mM creatinine; P < 0.05) concentrations than of those who were above -1 SD. There was no difference in these parameters between TNG and GD patients. No correlation was seen between serum IL-6 and OC or DPD. OC and DPD values were not different from controls in the hypothyroid group (Table 2Go).


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  		Table 2. Biochemical parameters of bone turnover in thyroid function disorders

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
We have shown that IL-6 levels are increased in the circulation in hyperthyroid women independent of the etiology of thyroid hyperfunction. Hypothyroidism did not significantly reduce serum IL-6. In hyperthyroidism, increased serum IL-6 could originate from several sources including the thyroid gland, blood mononuclear cells, and bone tissue.

Serum IL-6 has been reported to be increased in subacute thyroiditis (18). Serum IL-6 normalizes on remission of the disease, indicating that it is related to follicular cell damage. When these cells are damaged as a consequence of the presence of antithyroid antibodies, IL-6 is released into the circulation. It has been suggested that the magnitude of the increase may reflect the severity of the disease (19). In GD, although follicle cells are also able to express certain cytokines, intrathyroidal lymphocytes are the main source of IL-6 production (20). Weetmann et al. (14) found increased intrathyroidal but not serum IL-6 levels in a small group of patients with GD. Celik et al. (21) reported enhanced IL-6 serum levels in both GD and toxic multinodular goiter, which returned to normal after euthyroidism was restored with propylthiouracil treatment. Thus, increased intrathyroidal production of IL-6 in thyroid hyperfunction is one source of elevated IL-6 levels in serum.

Blood mononuclear cells produce IL-6 under normal basal conditions (15). These cells express thyroid hormone receptors (22). In the present study, we showed that basal IL-6 secretion from mononuclear cells is increased in both types of thyroid hyperfunction, but it can be further stimulated by PHA only in GD patients. In TNG, PHA was not effective in stimulating IL-6 production. This difference between GD and TNG might be because of the underlying immune disorders present in GD, however, this remains to be established. Our data raise the possibility that blood mononuclear cells make a major contribution to the increased serum IL-6 levels in hyperthyroidism. May et al. (23) has demonstrated complexed forms of IL-6 in human blood as a consequence of binding to plasma proteins. This binding could camouflage IL-6 immunoreactivity in serum in our assay and modify the results. However, we measured significantly increased levels of IL-6 in both serum and medium of mononuclear cell cultures of our patients.

IL-6 is produced by bone cells, especially by osteoblasts (13). IL-6 stimulates bone resorption by enhancing osteoclast proliferation and differentiation (8). In vitro, thyroid hormones do not stimulate IL-6 production directly in fetal rat limb bones (24). However, in the presence of physiological concentrations of thyroid hormones, the IL-1-stimulated IL-6 response, and bone resorption is greatly increased in these cultures (24). Thus, the increased levels of serum IL-6 in our present study may be at least partly a result of this permissive action of thyroid hormones in bone.

IL-6 has been suggested to serve as a paracrine mediator of estrogen action on bone cells (7). Estrogen withdrawal induces elevated IL-6 production by murine bone cells (25). Estrogen also inhibits IL-6 production in human osteoblastic cells (13). This effect seems to be mediated by an inhibitory effect of estrogen on the IL-6 gene promoter (26). In our study, the effect of menopause, i.e. estrogen deficiency, resulted in increased serum IL-6 levels in healthy postmenopausal women. It is interesting that no difference was seen in pre- and postmenopausal IL-6 levels in the hyperthyroid group. It may be that in hyperthyroidism IL-6 production is maximally stimulated even before menopause and cannot be further stimulated by estrogen deficiency. The lack of increase in IL-6 levels after menopause in the hypothyroid group may reflect the necessity of thyroid hormones for IL-6 production.

Appendicular BMC of hyperthyroid women was reduced in our study. High bone turnover was reflected in this group by increased biochemical markers of bone metabolism, i.e. serum osteocalcin and urinary cross-link excretion. Although there was no correlation between serum IL-6 and BMC, patients with the lowest BMC had the most elevated IL-6 levels. These data are consistent with studies implicating IL-6 in the elevated bone turnover resulting from estrogen deficiency (27, 28, 29). On the other hand, another study found no difference in IL-6 production by osteoblasts cultured from osteoporotic and nonosteoporotic normal women (30). In the osteoporotic group, the amount of IL-6 produced by osteoblasts did not correlate with the bone loss of patients as assessed by bone histomorphometry. We likewise could not show a correlation between serum IL-6 and bone loss, but did find significantly increased levels in the osteoporotic hyperthyroid patients. Serum OC and urinary DPD were also significantly increased in this subset of patients compared with hyperthyroid patients with normal BMC. The increased bone turnover in osteoporotic hyperthyroid patients accompanied by significantly elevated serum IL-6 raises the possibility that this cytokine plays a major role in thyroid hormone-stimulated bone loss.

Thyroid hormones have both anabolic and catabolic effects on bone. Anabolic effects, which are important for normal growth and the maintenance of bone tissue integrity, may be mediated through insulin-like growth factors (31). Based on our data, deleterious effects of thyroid hormones on bone tissue might be mediated by IL-6.


   Acknowledgments
 
We thank Ms. Veronika Reiner Szabone for excellent technical assistance.


   Footnotes
 
1 This work was supported by NIH Grants Fogarty R03-TW-00167-01, OTKA-1051, and ETK-K-126/95. Back

2 Recipient of stipend support from NIH Grant DK-45269. Back

Received July 8, 1996.

Revised August 22, 1996.

Accepted August 27, 1996.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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