scholarly journals Hyperthyroidism and Hypothyroidism in Male Mice and Their Effects on Bone Mass, Bone Turnover, and the Wnt Inhibitors Sclerostin and Dickkopf-1

Endocrinology ◽  
2015 ◽  
Vol 156 (10) ◽  
pp. 3517-3527 ◽  
Author(s):  
Elena Tsourdi ◽  
Eddy Rijntjes ◽  
Josef Köhrle ◽  
Lorenz C. Hofbauer ◽  
Martina Rauner
Keyword(s):  
Thyroid Hormone ◽  
Bone Density ◽  
Bone Mass ◽  
Bone Turnover ◽  
Thyroid Hormones ◽  
Wnt Signaling ◽  
Cortical Bone ◽  
Bone Remodeling ◽  
Wnt Inhibitors ◽  
Dickkopf 1

Thyroid hormones are key regulators of bone homeostasis, and Wnt signaling has been implicated in thyroid hormone-associated bone loss. Here we tested whether hyperthyroidism and hypothyroidism interfere with dickkopf-1 (DKK1) and sclerostin, two inhibitors of Wnt signaling. Twelve-week-old male C57BL/6 mice were rendered either hyperthyroid or hypothyroid. Hyperthyroid mice displayed decreased trabecular (−54%, P < .001) and cortical bone density (−5%, P < .05) and reduced cortical thickness (−15%, P < .001), whereas hypothyroid mice showed a higher trabecular bone density (+26%, P < .001) with unchanged cortical bone parameters. Histomorphometry and biochemical markers of bone remodeling indicated high bone turnover in hyperthyroid mice and low bone turnover in hypothyroid mice. In vivo, serum DKK1 concentrations were decreased in hyperthyroid mice (−24%, P < .001) and increased in hypothyroid mice (+18%, P < .01). The increase of the number of DKK1-positive cells in hypothyroid mice was confirmed at the tissue level. Interestingly, sclerostin was increased in both disease models, although to a higher extent in hyperthyroid mice (+50%, P < .001, and +24%, P < .05). Serum sclerostin concentrations adjusted for bone mass were increased by 3.3-fold in hyperthyroid (P < .001) but not in hypothyroid mice. Consistently, sclerostin mRNA expression and the number of sclerostin-positive cells were increased in hyperthyroid but not in hypothyroid mice. Our data show that thyroid hormone-induced changes in bone remodeling are associated with a divergent regulation of DKK1 and sclerostin. Thus, the modulation of Wnt signaling by thyroid hormones may contribute to thyroid hormone-associated bone disease and altered expression of Wnt inhibitors may emerge as potential therapeutic targets.

scholarly journals Thyroid hormone status within the physiological range affects bone mass and density in healthy men at the age of peak bone mass

2011 ◽  
Vol 164 (6) ◽  
pp. 1027-1034 ◽  
Author(s):  
Greet Roef ◽  
Bruno Lapauw ◽  
Stefan Goemaere ◽  
Hans Zmierczak ◽  
Tom Fiers ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Bone Density ◽  
Bone Mass ◽  
Thyroid Hormones ◽  
Cortical Bone ◽  
Bone Mineral ◽  
Peak Bone Mass ◽  
Bone Area ◽  
Mineral Density ◽  
Healthy Men

ContextThe hormonal factors involved in the regulation of peak bone mass (PBM) in men have not been fully investigated. Apart from gonadal steroids and somatotropic hormones, thyroid hormones are known to affect bone maturation and homeostasis and are additional candidate determinants of adult bone mass.ObjectiveWe aimed to investigate between-subject physiological variation in free and total thyroid hormone concentrations, TSH, and thyroid binding globulin (TBG) in relation to parameters of bone mass, geometry, and mineral density in healthy men at the age of PBM.Design and settingWe recruited 677 healthy male siblings aged 25–45 years in a cross-sectional, population-based study. Areal and volumetric bone parameters were determined using dual-energy x-ray absorptiometry (DXA) and peripheral quantitative computed tomography (pQCT). Total and free thyroid hormones, TBG, and TSH were determined using immunoassays.ResultsFree and total thyroid hormone concentrations were inversely associated with bone mineral density (BMD) and bone mineral content (BMC) at the hip and total body (free triiodothyronine (FT3), total T3 (TT3), and total T4 (TT4)) and at the spine (FT3). TBG was negatively associated with BMC and areal BMD at all sites. At the radius, cortical bone area was inversely associated with TT3, TT4, and TBG, and trabecular bone density was inversely associated with free thyroxine, TT4, and TBG. We observed inverse associations between cortical bone area at the mid-tibia and FT3, TT3, TT4, and TBG. No associations between TSH and DXA or pQCT measurements were found.ConclusionIn healthy men at the age of PBM, between-subject variation in thyroid hormone concentrations affects bone density, with higher levels of FT3, TT3, TT4, and TBG being associated with less favorable bone density and content.

Thyroid Hormone Actions and Bone Remodeling – The Role of the Wnt Signaling Pathway

2020 ◽  
Vol 128 (06/07) ◽  
pp. 450-454
Author(s):  
Franziska Lademann ◽  
Elena Tsourdi ◽  
Lorenz C. Hofbauer ◽  
Martina Rauner
Keyword(s):  
Thyroid Hormone ◽  
Bone Resorption ◽  
Bone Mass ◽  
Thyroid Hormones ◽  
Wnt Signaling ◽  
Signaling Pathway ◽  
Bone Development ◽  
Wnt Signaling Pathway ◽  
Bone Homeostasis ◽  
Normal Thyroid Function

AbstractThyroid hormones are indispensable for bone development and growth. Also in adults, bone mass maintenance is under the control of thyroid hormones. Preclinical and clinical studies established untreated hyperthyroidism as a cause for secondary osteoporosis with increased fracture risk. Thus, normal thyroid function is essential for bone health. Mechanistically, thyroid hormone excess accelerates bone turnover with predominant bone resorption. How thyroid hormones affect osteoblast and osteoclast functions, however, still remains ill-defined. The Wnt signaling pathway is a major determinant of bone mass and strength as it promotes osteoblastogenesis and bone formation, while inhibiting bone resorption. So far, only few studies investigated a possible link between thyroid hormones, bone metabolism and the Wnt pathway. In this review, we summarize the literature linking thyroid hormones to bone homeostasis through Wnt signaling and discuss its potential as a therapeutic approach to treat hyperthyroidism-induced bone loss.

scholarly journals The Role of Dickkopf-1 in Thyroid Hormone–Induced Changes of Bone Remodeling in Male Mice

Endocrinology ◽  
2019 ◽  
Vol 160 (3) ◽  
pp. 664-674 ◽  
Author(s):  
Elena Tsourdi ◽  
Juliane Colditz ◽  
Franziska Lademann ◽  
Eddy Rijntjes ◽  
Josef Köhrle ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Bone Mass ◽  
Bone Turnover ◽  
Knockout Mice ◽  
Bone Volume ◽  
Bone Homeostasis ◽  
Male Mice ◽  
Induced Changes ◽  
Dickkopf 1

Abstract Thyroid hormones regulate bone homeostasis, and exogenously induced hyperthyroidism and hypothyroidism in mice was recently found to be associated with an altered expression of the Wnt inhibitor Dickkopf-1 (Dkk1), a determinant of bone mass. Here, we assessed the role of Dkk1 in thyroid hormone–induced changes in bone using conditional Dkk1 knockout mice. Male mice with a global (Dkk1fl/fl;Rosa26-CreERT2) or osteocyte-specific (Dkk1fl/fl;Dmp1:Cre) deletion of Dkk1 were pharmacologically rendered hypothyroid or hyperthyroid. The bone phenotype was analyzed using micro-CT analysis, dynamic histomorphometry, and serum concentrations of bone turnover markers. Hypothyroid and hyperthyroid Cre-negative mice of either Cre line revealed the expected changes in bone volume with hypothyroid mice displaying a 40% to 60% increase in vertebral trabecular bone volume, while hyperthyroid mice lost 45% to 60% of bone volume. Similar changes were observed at the spine. Interestingly, Cre-positive mice of both lines did not gain or lose as much bone at the femur when rendered hypothyroid or hyperthyroid. While Cre-negative hypothyroid mice gained 80% to 100% bone volume, Cre-positive hypothyroid mice only increased their bone volume by 55% to 90%. Similarly, Cre-negative hyperthyroid mice lost 74% to 79% bone, while Cre-positive hyperthyroid mice merely lost 40% to 54%. Despite these site-specific differences, both global and osteocyte-specific Dkk1 knockout mice displayed similar changes in bone turnover as their Cre-negative controls in the hypothyroid and hyperthyroid states. While osteoblast and osteoclast parameters were increased in hyperthyroidism, hypothyroidism potently suppressed bone cell activities. Loss of Dkk1 is not sufficient to fully reverse thyroid hormone–induced changes in bone mass and bone turnover.

Dickkopf-1 is dispensable for thyroid hormone-induced changes in bone remodeling

2019 ◽  
Author(s):  
E Tsourdi ◽  
J Colditz ◽  
F Lademann ◽  
E Rijntjes ◽  
J Köhrle ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Bone Remodeling ◽  
Induced Changes ◽  
Dickkopf 1

scholarly journals Responses of Trabecular and Cortical Bone Turnover and Bone Mass and Strength to Bisphosphonate YH529 in Ovariohysterectomized Beagles with Calcium Restriction

1998 ◽  
Vol 13 (6) ◽  
pp. 1011-1022 ◽  
Author(s):  
Yasushi Yoshida ◽  
Atsuko Moriya ◽  
Kazuyuki Kitamura ◽  
Mizuho Inazu ◽  
Nobukazu Okimoto ◽  
...  
Keyword(s):  
Bone Mass ◽  
Bone Turnover ◽  
Cortical Bone

scholarly journals R-spondin 3 deletion favors Erk phosphorylation to enhance Wnt signaling and bone formation

2021 ◽  
Author(s):  
Kenichi Nagano ◽  
Kei Yamana ◽  
Hiroaki Saito ◽  
Riku Kiviranta ◽  
Ana Clara Pedroni ◽  
...  
Keyword(s):  
Bone Density ◽  
Bone Formation ◽  
Bone Mass ◽  
Wnt Signaling ◽  
Erk Signaling ◽  
Canonical Wnt Signaling ◽  
Erk Phosphorylation ◽  
High Bone ◽  
Canonical Wnt

Abstract Activation of Wnt signaling leads to high bone density. The R-spondin family of four secreted glycoproteins (Rspo1-4) amplifies Wnt signaling. In humans, RSPO3 variants are strongly associated with bone density, but how RSPO3 affects skeletal homeostasis is not fully understood. Here we show that in mice Rspo3 haplo-insufficiency or its targeted deletion in osteoprogenitors lead to an increase in bone formation and bone mass. Contrary to expectations, Rspo3 haplo-insufficiency results in canonical Wnt signaling activation. Using mouse embryonic fibroblasts we show that Rspo3 deficiency leads to activation of Erk signaling, stabilizing β-catenin. Furthermore, Rspo3 haplo-insufficiency impairs Dkk1 efficacy in blocking canonical Wnt signaling and prevents the in vivo inhibition of bone formation and bone mass induced by osteoblast-targeted expression of Dkk1. We conclude that Rspo3 haplo-insufficiency/deficiency boosts canonical Wnt signaling by activating Erk signaling and impairing Dkk1’s inhibitory activity, which in turn lead to increased bone formation and bone mass.

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