Pten deletion in Dmp1-expressing cells does not rescue the osteopenic effects of Wnt/β-catenin suppression
| Autor: | Daniel J. Horan, Alexander G. Robling, April M. Hoggatt, Kyung Eun Lim, Whitney A. Bullock, Frederick M. Pavalko, Hiroki Yokota |
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| Rok vydání: | 2019 |
| Předmět: |
Physiology
Clinical Biochemistry Population Article Mice Phosphatidylinositol 3-Kinases Osteogenesis Neoplasms Bone cell medicine PTEN Animals Humans education Protein kinase B Wnt Signaling Pathway PI3K/AKT/mTOR pathway beta Catenin Cell Proliferation education.field_of_study Extracellular Matrix Proteins Osteoblasts biology Wnt signaling pathway PTEN Phosphohydrolase Osteoblast Cell Biology Bone Diseases Metabolic Disease Models Animal medicine.anatomical_structure Catenin biology.protein Cancer research Proto-Oncogene Proteins c-akt |
| Zdroj: | J Cell Physiol |
| ISSN: | 1097-4652 |
| Popis: | Skeletal homeostasis is sensitive to perturbations in Wnt signaling. Beyond its role in 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 in order to delete Pten alone, β-catenin alone, or both genes, from the late-stage osteoblast/osteocyte population. 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. |
| Databáze: | OpenAIRE |
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