Sclerostin and dickkopf-1 are distinctly regulated by hyperthyroidism and hypothyroidism in mice

Abstract

Introduction: The regulation of skeletal development through thyroid hormones (TH) remains poorly understood. Here, we tested the hypothesis that TH alter bone turnover by modulating dickkopf-1 (DKK1) and sclerostin (SOST), two inhibitors of the Wnt signaling pathway. Methods: We performed µCT, dynamic histomorphometry, and assessed bone remodeling markers and DKK1 and SOST levels in twelve-week old male hyperthyroid and hypothyroid C57BL/6 mice. The expression of osteoblast differentiation genes was evaluated using qPCR after treating murine osteoblasts with triiodothyronine (T3). Wnt activity was determined using a TCF/LEF promoter construct in MC3T3 cells exposed to T3. Results: Hyperthyroid mice showed a reduced trabecular (-54%, p < 0.001) and cortical bone density (-5%, p < 0.05) and cortical thickness (-15%, p < 0.001). In hypothyroid mice, trabecular bone density was higher (+26%, p < 0.001), but cortical bone parameters were unchanged. Histology, histomorphometry, and markers of bone remodeling (P1NP, CTX) indicated a high bone turnover in hyperthyroid and a low bone turnover in hypothyroid mice. Stimulation of osteoblasts with T3 led to an activation of Wnt signaling. Although serum DKK1 was decreased in hyperthyroid mice (-25%, p < 0.001) and increased in hypothyroid mice (+22%, p < 0.001), SOST was increased in both disease models. While SOST correlated positively with the bone density in euthyroid mice, this turned into a negative correlation when calculated across treatment groups. DKK1 did not correlate with bone density or bone remodeling parameters when calculated per treatment group. However, across all groups, DKK1 was positively correlated with BMD and strongly negatively correlated with bone formation and resorption parameters. SOST and DKK1 negatively correlated with each other. Conclusions: TH-induced changes in bone remodeling are distinctively associated with an altered Wnt activity in vitro and in vivo and a divergent regulation of DKK1 and SOST.