The Role of Dickkopf-1 in Thyroid Hormone-Induced Changes of Bone Remodeling in Male Mice.

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.

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