Department of Medicine III, Technische Universität Dresden Medical Center, Dresden, Germany.
Center for Healthy Aging, Technische Universität Dresden Medical Center, Dresden, Germany.
Endocrinology. 2019 Mar 1;160(3):664-674. doi: 10.1210/en.2018-00998.
Thyroid hormones regulate bone homeostasis, and exogenously induced hyperthyroidism and hypothyroidism in mice was recently found to be associated with an altered expression of the Wnt inhibitor Dickkopf-1 (Dkk1), a determinant of bone mass. Here, we assessed the role of Dkk1 in thyroid hormone-induced changes in bone using conditional Dkk1 knockout mice. Male mice with a global (Dkk1fl/fl;Rosa26-CreERT2) or osteocyte-specific (Dkk1fl/fl;Dmp1:Cre) deletion of Dkk1 were pharmacologically rendered hypothyroid or hyperthyroid. The bone phenotype was analyzed using micro-CT analysis, dynamic histomorphometry, and serum concentrations of bone turnover markers. Hypothyroid and hyperthyroid Cre-negative mice of either Cre line revealed the expected changes in bone volume with hypothyroid mice displaying a 40% to 60% increase in vertebral trabecular bone volume, while hyperthyroid mice lost 45% to 60% of bone volume. Similar changes were observed at the spine. Interestingly, Cre-positive mice of both lines did not gain or lose as much bone at the femur when rendered hypothyroid or hyperthyroid. While Cre-negative hypothyroid mice gained 80% to 100% bone volume, Cre-positive hypothyroid mice only increased their bone volume by 55% to 90%. Similarly, Cre-negative hyperthyroid mice lost 74% to 79% bone, while Cre-positive hyperthyroid mice merely lost 40% to 54%. Despite these site-specific differences, both global and osteocyte-specific Dkk1 knockout mice displayed similar changes in bone turnover as their Cre-negative controls in the hypothyroid and hyperthyroid states. While osteoblast and osteoclast parameters were increased in hyperthyroidism, hypothyroidism potently suppressed bone cell activities. Loss of Dkk1 is not sufficient to fully reverse thyroid hormone-induced changes in bone mass and bone turnover.
甲状腺激素调节骨稳态，最近发现，在外源性诱导的甲亢和甲减小鼠中，Wnt 抑制剂 Dickkopf-1（Dkk1）的表达发生改变，而 Dkk1 是骨量的决定因素。在此，我们使用条件性 Dkk1 敲除小鼠评估了 Dkk1 在甲状腺激素诱导的骨变化中的作用。雄性小鼠全身性（Dkk1fl/fl;Rosa26-CreERT2）或成骨细胞特异性（Dkk1fl/fl;Dmp1:Cre）敲除 Dkk1，并用药物诱导其发生甲状腺功能减退或甲状腺功能亢进。使用 micro-CT 分析、动态组织形态计量学和血清骨转换标志物浓度来分析骨表型。两种 Cre 线的 Cre 阴性对照甲状腺功能减退和甲状腺功能亢进小鼠均表现出预期的骨量变化，甲状腺功能减退小鼠的椎体小梁骨量增加 40%至 60%，而甲状腺功能亢进小鼠的骨量减少 45%至 60%。在脊柱也观察到了类似的变化。有趣的是，两条线的 Cre 阳性小鼠在甲状腺功能减退或甲状腺功能亢进时，股骨的骨量并没有增加或减少那么多。虽然 Cre 阴性甲状腺功能减退小鼠的骨量增加了 80%至 100%，但 Cre 阳性甲状腺功能减退小鼠的骨量仅增加了 55%至 90%。同样，Cre 阴性甲状腺功能亢进小鼠的骨量减少了 74%至 79%，而 Cre 阳性甲状腺功能亢进小鼠的骨量仅减少了 40%至 54%。尽管存在这些部位特异性差异，但在甲状腺功能减退和甲状腺功能亢进状态下，全身性和成骨细胞特异性 Dkk1 敲除小鼠的骨转换均表现出与 Cre 阴性对照相似的变化。在甲状腺功能亢进症中，成骨细胞和破骨细胞参数增加，而甲状腺功能减退症则强烈抑制骨细胞的活性。Dkk1 的缺失不足以完全逆转甲状腺激素引起的骨量和骨转换变化。
