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

Wnt 信号传导在经典和非经典甲状腺激素对骨的作用 (T0-T4) 中的作用

• 批准号: 279702646
• 负责人: Professor Dr. Lorenz C. Hofbauer
• 金额: --
• 依托单位: Bereich Endokrinologie, Diabetes und Knochenstoffwechselerkrankungen
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/279702646?language=en
• 关键词: Role; Wnt; signaling; classical; non

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.

甲状腺激素（TH）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。甲状腺功能亢进症通过增强成骨细胞和破骨细胞功能增加骨重建，有利于骨吸收。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，TH相关的甲状腺素（TAMs）已被确定也发挥TH样作用，但他们的存在和可能对骨的影响是未知的。基于我们的初步数据，TH过量调节Wnt抑制剂dickkopf-1（DKK 1）和sclerostin的产生，我们假设Wnt信号通路由TH调节，并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TAM在骨中起作用，并且像经典TH一样也调节骨重建和Wnt信号传导。为了验证我们的假设，我们将研究经典TH对Wnt抑制剂DKK 1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。使用针对sclerostin的中和抗体，我们将能够评估甲状腺功能亢进症中Wnt通路调节的治疗潜力。最后，我们将讨论TAMs对骨重建的作用以及DKK 1和sclerostin的调节。详细了解甲亢引起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。