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

甲状腺激素(TH)是骨骼发育的关键调节因素，甲状腺疾病与骨质疏松性骨折的增加有关。甲状腺功能亢进症通过增强成骨细胞和破骨细胞功能，促进骨吸收，从而增加骨重建。然而，其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，与TH相关的甲状腺胺(TAMs)也被发现具有TH样的作用，但它们的存在及其对骨骼的可能作用尚不清楚。根据我们的初步数据，TH过量调节了Wnt抑制物Dickkopf-1(Dkk1)和skerostin的产生，我们假设Wnt信号通路受TH的调节，并关键决定了它们对成骨细胞功能和骨重建的影响。此外，我们假设TAMs在骨中起作用，像经典的TH一样，也调节骨重建和Wnt信号。为了验证我们的假设，我们将检查经典的TH对Wnt抑制物Dkk1和skerostin表达的影响，这两个关键的骨稳态调节因子，并确定它们调节和影响骨转换的潜在机制。使用针对硬化素的中和抗体，我们将能够评估Wnt通路在甲状腺功能亢进症中的治疗潜力。最后，我们将讨论TAMs在骨重建中的作用以及对Dkk1和skerostin的调节。了解甲状腺功能亢进导致骨丢失的分子机制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.