Hyperthyroidism and Hypothyroidism in Male Mice and Their Effects on Bone Mass, Bone Turnover, and the Wnt Inhibitors Sclerostin and Dickkopf-1

Endocrinology. 2015 Oct;156(10):3517-27. doi: 10.1210/en.2015-1073. Epub 2015 Jul 28.

Abstract

Thyroid hormones are key regulators of bone homeostasis, and Wnt signaling has been implicated in thyroid hormone-associated bone loss. Here we tested whether hyperthyroidism and hypothyroidism interfere with dickkopf-1 (DKK1) and sclerostin, two inhibitors of Wnt signaling. Twelve-week-old male C57BL/6 mice were rendered either hyperthyroid or hypothyroid. Hyperthyroid mice displayed decreased trabecular (-54%, P < .001) and cortical bone density (-5%, P < .05) and reduced cortical thickness (-15%, P < .001), whereas hypothyroid mice showed a higher trabecular bone density (+26%, P < .001) with unchanged cortical bone parameters. Histomorphometry and biochemical markers of bone remodeling indicated high bone turnover in hyperthyroid mice and low bone turnover in hypothyroid mice. In vivo, serum DKK1 concentrations were decreased in hyperthyroid mice (-24%, P < .001) and increased in hypothyroid mice (+18%, P < .01). The increase of the number of DKK1-positive cells in hypothyroid mice was confirmed at the tissue level. Interestingly, sclerostin was increased in both disease models, although to a higher extent in hyperthyroid mice (+50%, P < .001, and +24%, P < .05). Serum sclerostin concentrations adjusted for bone mass were increased by 3.3-fold in hyperthyroid (P < .001) but not in hypothyroid mice. Consistently, sclerostin mRNA expression and the number of sclerostin-positive cells were increased in hyperthyroid but not in hypothyroid mice. Our data show that thyroid hormone-induced changes in bone remodeling are associated with a divergent regulation of DKK1 and sclerostin. Thus, the modulation of Wnt signaling by thyroid hormones may contribute to thyroid hormone-associated bone disease and altered expression of Wnt inhibitors may emerge as potential therapeutic targets.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Animals
  • Bone Density
  • Bone Marrow Cells / cytology
  • Bone Remodeling*
  • Bone Resorption
  • Bone and Bones / metabolism*
  • Cell Differentiation
  • Glycoproteins / metabolism*
  • Hyperthyroidism / physiopathology*
  • Hypothyroidism / physiopathology*
  • Immunohistochemistry
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Osteoblasts / cytology
  • Signal Transduction
  • Thyroxine / metabolism
  • Triiodothyronine / metabolism
  • Wnt Proteins / metabolism*
  • X-Ray Microtomography

Substances

  • Dkk1 protein, mouse
  • Glycoproteins
  • Intercellular Signaling Peptides and Proteins
  • Sost protein, mouse
  • Wnt Proteins
  • Triiodothyronine
  • Thyroxine