Role of Wnt signaling in classical and non-classical thyroid hormone actions (T0-T4) on bone

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Thyroid hormones (THs) are key regulators of skeletal development and thyroid diseases have been associated with increased osteoporotic fractures. Hyperthyroidism increases bone remodeling by enhancing osteoblast and osteoclast functions, favoring bone resorption. Yet, the underlying mechanisms remain poorly understood, in particular with regard to their effects on osteoblast function. Recently, TH-related thyronamines (TAMs) have been identified to also exert TH-like actions, but their presence and possible effects on bone are unknown. Based on our preliminary data that TH excess modulates the production of the Wnt inhibitors dickkopf-1 (DKK1) and sclerostin, we hypothesize that the Wnt signaling pathway is modulated by THs and critically determines their effects on osteoblast function and bone remodeling. Moreover, we postulate that TAMs are operative in bone and like classical TH also modulate bone remodeling and Wnt signaling. To test our hypotheses, we will examine the effects of classical THs on the expression of the Wnt inhibitors DKK1 and sclerostin, two key regulators of bone homeostasis, and identify the underlying mechanisms of their regulation and impact on bone turnover. Using neutralizing antibodies against sclerostin, we will be able to evaluate the therapeutic potential of the modulation of the Wnt pathway in hyperthyroidism. Finally, we will address the role of TAMs on bone remodeling and the regulation of DKK1 and sclerostin. A detailed knowledge of the molecular mechanisms underlying hyperthyroidism-induced bone loss may help to better protect bone mass in patients with thyroid disease.