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

甲状腺激素是骨骼发育的关键调节因子，甲状腺疾病与骨质疏松性骨折的增加有关。甲亢通过增强成骨细胞和破骨细胞功能，促进骨吸收，从而增加骨重塑。然而，潜在的机制仍然知之甚少，特别是关于它们对成骨细胞功能的影响。最近，已确定th相关的甲状腺胺类（tam）也发挥th样作用，但它们对骨骼的存在和可能的影响尚不清楚。根据我们的初步数据，TH过量调节Wnt抑制剂dickkopf-1 （DKK1）和sclerostin的产生，我们假设Wnt信号通路由TH调节，并关键地决定了它们对成骨细胞功能和骨重塑的影响。此外，我们假设tam在骨中起作用，并且像经典TH一样也调节骨重塑和Wnt信号传导。为了验证我们的假设，我们将研究经典三萜类化合物对Wnt抑制剂DKK1和sclerostin（骨稳态的两个关键调节因子）表达的影响，并确定其调节和影响骨转换的潜在机制。使用抗硬化蛋白的中和抗体，我们将能够评估调节Wnt通路在甲状腺功能亢进中的治疗潜力。最后，我们将讨论tam在骨重塑中的作用以及DKK1和硬化蛋白的调控。对甲状腺功能亢进导致的骨质流失的分子机制的详细了解可能有助于更好地保护甲状腺疾病患者的骨量。

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.