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Suppression of Wnt signaling by Dkk1 attenuates PTH-mediated stromal cell response and new bone formation

Jun Guo1, Minlin Liu, Dehong Yang

  • 1Endocrine Unit, Massachusetts General Hospital, Boston, MA 02114, USA.

Cell Metabolism
|February 10, 2010
PubMed

Insights

Parathyroid hormone (PTH) normally suppresses Dickkopf 1 (Dkk1) to promote bone formation. Even when Dkk1 is overexpressed, PTH can still activate Wnt signaling, though bone formation is impaired.

Area of Science:

  • Endocrinology
  • Bone Biology
  • Molecular Signaling

Background:

  • Parathyroid hormone (PTH) plays a crucial role in calcium homeostasis and bone metabolism.
  • Dickkopf 1 (Dkk1) is a known inhibitor of the Wnt signaling pathway, which is vital for bone formation.
  • The precise role of PTH-mediated suppression of Dkk1 in regulating Wnt signaling and bone anabolism remains incompletely understood.

Purpose of the Study:

  • To investigate whether the suppression of Dickkopf 1 (Dkk1) by parathyroid hormone (PTH) is essential for PTH-induced Wnt signaling and bone formation.
  • To elucidate the impact of osteoblast-specific Dkk1 overexpression on PTH's effects in vivo and in vitro.

Main Methods:

  • Generation and analysis of transgenic mice overexpressing Dkk1 specifically in osteoblasts (Dkk1 mice).
  • Assessment of bone phenotype, osteoblast and osteoclast activity, and response to hyperparathyroidism models (low-calcium diet, other models) in Dkk1 mice and wild-type littermates.
  • In vitro studies using cultured MC3T3E1 preosteoblastic cells to examine PTH's effects on Dkk1 expression, beta-catenin phosphorylation, and Lef1 expression.

Main Results:

  • Dkk1 mice exhibited osteopenia characterized by abnormal osteoblast and osteoclast activity.
  • In hyperparathyroidism models, Dkk1 mice failed to exhibit the typical peritrabecular stromal cell response ('osteitis fibrosis') and new bone formation observed in wild-type mice.
  • Despite Dkk1 overexpression, PTH effectively activated Wnt signaling in both Dkk1 mice and cultured osteoblastic cells, and in vitro, PTH suppressed Dkk1, induced beta-catenin phosphorylation, and enhanced Lef1 expression.

Conclusions:

  • The complete anabolic actions of parathyroid hormone (PTH) necessitate an intact Wnt signaling pathway.
  • PTH is capable of activating the Wnt pathway even in the presence of Dkk1 overexpression.
  • While PTH-mediated suppression of Dkk1 is important for robust bone formation, Wnt pathway activation by PTH can occur independently of complete Dkk1 inhibition.

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