Direct activation of PI3K in osteoblasts and osteocytes strengthens murine bone through sex-specific actions on cortical surfaces

Journal article


Wee, Natalie K. Y., McGregor, Narelle E., Walker, Emma C., Poulton, Ingrid J., Dang, Michelle Kieu Mi, Gooi, Jonathan H., Phillips, Wayne A. and Sims, Natalie A.. (2024). Direct activation of PI3K in osteoblasts and osteocytes strengthens murine bone through sex-specific actions on cortical surfaces. Journal of Bone and Mineral Research. 39(8), pp. 1174-1187. https://doi.org/10.1093/jbmr/zjae102
AuthorsWee, Natalie K. Y., McGregor, Narelle E., Walker, Emma C., Poulton, Ingrid J., Dang, Michelle Kieu Mi, Gooi, Jonathan H., Phillips, Wayne A. and Sims, Natalie A.
Abstract

Intracellular phosphoinositide 3-kinase (PI3K) signaling is activated by multiple bone-active receptors. Genetic mutations activating PI3K signaling are associated with clinical syndromes of tissue overgrowth in multiple organs, often including the skeleton. While one formation is increased by removing the PI3K inhibitor (phosphatase and TENsin homolog deleted on chromosome 10 (PTEN)), the effect of direct PI3K activation in the osteoblast lineage has not been reported. We introduced a known gain-of-function mutation in Pik3ca, the gene encoding the p110α catalytic subunit of PI3K, in osteocytes and late osteoblasts using the dentin matrix protein-1 Cre (Dmp1Cre) mouse and assessed the skeletal phenotype. Femur shape was grossly normal, but cortical thickness was significantly greater in both male and female Dmp1Cre.Pik3caH1047R mice, leading to almost doubled bone strength at 12 wk of age. Both sexes had smaller marrow areas from 6 wk of age. Female mice also exhibited greater cross-sectional area, which continued to increase until 24 wk of age, resulting in a further increase in bone strength. Although both male and female mice had increased endocortical mineralizing surface, only female mice had increased periosteal mineralizing surface.

The bone formed in the Dmp1Cre.Pik3caH1047R mice showed no increase in intracortical remodeling nor any defect in cortical bone consolidation. In contrast, on both endocortical and periosteal surfaces, there was more lamellar bone formation, including highly organized osteocyte networks extending along the entire surface at a greater thickness than in control mice. In conclusion, direct activation of PI3Kα in cells targeted by Dmp1Cre leads to high cortical bone mass and strength with abundant lamellar cortical bone in female and male mice with no increase in intracortical remodeling. This differs from the effect of PTEN deletion in the same cells, suggesting that activating PI3Kα in osteoblasts and osteocytes may be a more suitable target to promote formation of lamellar bone.

Keywordsosteoblast; osteocyte; cortical bone; bone strength; sex differences
Year2024
JournalJournal of Bone and Mineral Research
Journal citation39 (8), pp. 1174-1187
PublisherOxford University Press
ISSN0884-0431
Digital Object Identifier (DOI)https://doi.org/10.1093/jbmr/zjae102
PubMed ID38959852
Scopus EID2-s2.0-85201996898
Page range1174-1187
FunderMarion and E. H. Flack Trust
St Vincent’s Institute of Medical Research
Weary Dunlop Foundation
National Health and Medical Research Council (NHMRC)
Operational Infrastructure Support (OIS) Program, Victorian Government
Publisher's version
License
All rights reserved
File Access Level
Controlled
Output statusPublished
Publication dates
Online03 Jul 2024
Publication process dates
Accepted01 Jul 2024
Deposited05 May 2025
Additional information

© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research. All rights reserved.

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