Pten deletion in Dmp1-expressing cells does not rescue the osteopenic effects of Wnt/β-catenin suppression

Kyung Eun Lim, April M. Hoggatt, Whitney A. Bullock, Daniel J. Horan, Hiroki Yokota, Frederick M. Pavalko, Alexander G. Robling

Research output: Contribution to journalArticle

Abstract

Skeletal homeostasis is sensitive to perturbations in Wnt signaling. Beyond its role in the bone, Wnt is a major target for pharmaceutical inhibition in a wide range of diseases, most notably cancers. Numerous clinical trials for Wnt-based candidates are currently underway, and Wnt inhibitors will likely soon be approved for clinical use. Given the bone-suppressive effects accompanying Wnt inhibition, there is a need to expose alternate pathways/molecules that can be targeted to counter the deleterious effects of Wnt inhibition on bone properties. Activation of the Pi3k/Akt pathway via Pten deletion is one possible osteoanabolic pathway to exploit. We investigated whether the osteopenic effects of β-catenin deletion from bone cells could be rescued by Pten deletion in the same cells. Mice carrying floxed alleles for Pten and β-catenin were bred to Dmp1-Cre mice to delete Pten alone, β-catenin alone, or both genes from the late-stage osteoblast/osteocyte population. The mice were assessed for bone mass, density, strength, and formation parameters to evaluate the potential rescue effect of Pten deletion in Wnt-impaired mice. Pten deletion resulted in high bone mass and β-catenin deletion resulted in low bone mass. Compound mutants had bone properties similar to β-catenin mutant mice, or surprisingly in some assays, were further compromised beyond β-catenin mutants. Pten inhibition, or one of its downstream nodes, is unlikely to protect against the bone-wasting effects of Wnt/βcat inhibition. Other avenues for preserving bone mass in the presence of Wnt inhibition should be explored to alleviate the skeletal side effects of Wnt inhibitor-based therapies.

Original languageEnglish (US)
JournalJournal of cellular physiology
DOIs
StateAccepted/In press - 2020

Keywords

  • Akt
  • Pten
  • Wnt
  • osteoporosis
  • β-catenin

ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Cell Biology

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