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

Abstract

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.

Hormonal and systemic regulation of sclerostin

“…This sclerostin decrease was associated with significant declines in biochemical markers of bone formation (osteocalcin; OCN) and resorption (CTX), and a simultaneous increase in PTH levels (P for each < 0.001) [50]. In a murine model of hyperthyroidism, sclerostin levels (both circulating blood levels and when excised bone was assessed for SOST mRNA expression) were increased relative to those of euthyroid mice, a finding which was particularly striking when considered in relation to the lower bone mass of the hyperthyroid mice (P<0.001) [51]. However, a recent study which examined thyroid stimulating hormone levels in two large German population-based cohorts did not identify any significant association between levels of thyroid stimulating hormone (TSH) and sclerostin [52].…”

Energy Metabolism in the Bone is Associated with Histomorphometric Changes in Rats with Hyperthyroidism

“…A clinical case–control study has shown that hyperthyroidism can cause net bone loss, decreased bone mineral density (BMD), and osteoporosis and increase the risk for fractures [1]. Both animal and clinical studies have shown that subjects with hyperthyroidism had higher bone resorption rates and bone formation marker levels [2-4] and that excessive levels of thyroid hormones might stimulate both osteoblast and osteoclast differentiation, however, the latter was more predominantly observed [5, 6]. Hyperthyroidism led to a higher frequency of bone remodelling.…”

Excesso de tiroxina materna associado ao hipertireoidismo pós-natal reduz o crescimento ósseo e o perfil proliferativo e angiogênico das cartilagens de crescimento de ratos

“…Ao contrário, neste estudo, a largura óssea se reduziu, sem alteração do crescimento longitudinal. Em camundongos machos adultos com hipertireoidismo, foi descrita redução na espessura da cortical femoral em decorrência da supremacia do processo de reabsorção frente à aposição óssea (Tsourdi et al, 2015). Embora não tenha sido escopo deste estudo avaliar a reabsorção óssea, pode-se sugerir que, no tecido ósseo trabecular, não houve supremacia de nenhum desses dois processos, uma vez que a quantidade de tecido ósseo trabecular foi semelhante entre grupos.…”

“…Essa sinalização ocorre via Wnt β-catenina, que é crucial para alinhar os planos de divisão e promover a formação das colunas dos condrócitos da zona de proliferação (Topczewski et al, 2001;Li e Dudley, 2009). Já foi descrito que os hormônios da tireoide ativam a via de sinalização Wnt β-catenina em cultivos de condrócitos da placa epifisária de ratos e regulam, em parte, a diferenciação terminal de condrócitos da placa epifisária (Wang et al, 2007). Dessa forma, as alterações na via de sinalização Wnt β-catenina pelos hormônios tireoidianos é uma das hipóteses para explicar a alteração na morfologia da placa epifisária observada nos animais submetidos ao excesso de tiroxina materna e pós-natal.…”