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.