Pten deletion in Dmp1‐expressing cells does not rescue the osteopenic effects of Wnt/β‐catenin suppression. Issue 12 (11th June 2020)

• Record Type: Journal Article
• Authors: Lim, Kyung‐Eun; Hoggatt, April M.; Bullock, Whitney A.; Horan, Daniel J.; Yokota, Hiroki; Pavalko, Frederick M.; Robling, Alexander G.
• Is Part Of: Journal of cellular physiology. Volume 235:Issue 12(2020:Dec.)
• Page Start: 9785
• Page End: 9794
• Publication Date: 2020-06-11
• Subjects: Akt -- osteoporosis -- Pten -- Wnt -- β‐catenin; Physiology -- Periodicals; Cell physiology -- Periodicals; 571.6
• DOI: 10.1002/jcp.29792
• Languages: English
• ISSNs: 0021-9541

Abstract

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.