Estrogens Modulate RANKL-RANK/Osteoprotegerin Mediated Interleukin-6 Effect on Thyrotoxicosis-related Bone Turnover in Mice

Abstract

Interleukin-6 has been shown to cause imbalance between bone resorption and formation in thyrotoxicosis. The aim of the present study was an attempt to estimate the influence of estrogens on thyrotoxicosis-related disturbances in bone turnover in relation to RANKL-RANK/osteoprotegerin system in IL-6 deficient mice. The study was performed on 56, 12-13 weeks old, female mice: C57BL/6J (wild-type; WT) and C57BL/6J (IL6-/-Kopf) (IL-6 knock-out; IL6KO). The mice were randomly divided into 8 groups with 7 mice in each one: 1. WT controls, 2. IL6KO controls, 3. WT mice with thyrotoxicosis, 4. IL6KO mice with thyrotoxicosis, 5. WT ovariectomized, 6. IL6KO ovariectomized, 7. WT ovariectomized mice with thyrotoxicosis, and 8. IL6KO ovariectomized mice with thyrotoxicosis. Experimental model of menopause was evoked by bilateral ovariectomy carried out in 8-9 weeks old mice. Thyrotoxicosis was induced by intraperitoneal injection of levothyroxine at a dose of 1 μg/g daily over 21 days. The serum levels of TRACP5b, osteocalcin, OPG, and RANKL were determined by ELISA. RANKL serum concentrations were elevated significantly in all groups of ovariectomized mice as compared to respective controls, however, in a minor degree in IL6KO thyrotoxic mice as compared to wild-type animals. Osteoprotegerin serum levels were significantly increased in all thyrotoxic groups of mice except ovariectomized IL6KO animals. To sum up, the results of the present study suggest that IL-6 plays a key role in stimulation of RANKL-RANK/OPG system and this effect is strongly enhanced in conditions of accelerated bone turnover such as thyrotoxicosis and/or estrogen depletion.

Levothyroxine enhances glucose clearance and blunts the onset of experimental type 1 diabetes mellitus in mice

“…until 24 weeks of age, when mice were killed (Spencer and West, 1961;Weinstein et al, 1991;Weinstein et al, 1994;Wistuba et al, 2007;Dong et al, 2010;Mysliwiec et al, 2011;Buras et al, 2014). Analysis of serum samples indicated that T4 concentration was increased in T4-treated mice (Supporting Information Figure S1A).…”

Adjunctive Antimicrobial Photodynamic Treatment of Experimentally Induced Periodontitis in Rats With Ovariectomy

“…11 Studies suggest that estrogen can modulate the RANKL-OPG system and increase levels of OPG, causing a decrease in the RANKL/OPG protein ratio. 12,13 Under certain circumstances, disequilibrium in the RANK/RANKL/OPG triad induces an enhanced activity of osteoclasts assessed by an increase in tartrate-resistant acid-phosphatase (TRAP) staining. 14,15 Because multinuclear TRAP-positive cells resorb bone, TRAP is a specific osteoclast differentiation marker.…”

Complications of Hyperthyroidism

“…These include a relative deficiency of insulin-like growth factor type I, dehydroepiandrosterone sulfate [287], vitamin D receptor (VDR) polymorphisms [288] and estrogen [289]. The question as to whether prolonged hyperthyroidism due to L-T4 treatment increases the risk of fractures also remains controversial.…”