Myeloid Lineage Ablation of Phlpp1 Regulates M-CSF Signaling and Tempers Bone Resorption in Female Mice
| Autor: | Kim C. Mansky, Jeyaram R. Damodaran, Ismael Y. Karkache, David H. H. Molstad, Elizabeth W. Bradley |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
medicine.medical_specialty
Myeloid QH301-705.5 Osteoporosis PDZ domain Catalysis Bone resorption Inorganic Chemistry Osteoclast Internal medicine Protein Kinase C (PKC) medicine Physical and Theoretical Chemistry Biology (General) Molecular Biology QD1-999 Spectroscopy PHLPP bone mass Chemistry Akt PH domain Organic Chemistry Osteoblast General Medicine medicine.disease Actin cytoskeleton osteoporosis MEK Computer Science Applications Resorption ERK medicine.anatomical_structure Endocrinology Ras-association domain sexual dimorphism osteoclast |
| Zdroj: | International Journal of Molecular Sciences, Vol 22, Iss 9702, p 9702 (2021) International Journal of Molecular Sciences Volume 22 Issue 18 |
| ISSN: | 1661-6596 1422-0067 |
| Popis: | Prior work demonstrated that Phlpp1 deficiency alters trabecular bone mass and enhances M-CSF responsiveness, but the cell types and requirement of Phlpp1 for this effect were unclear. To understand the function of Phlpp1 within myeloid lineage cells, we crossed Phlpp1 floxed mice with mice harboring LysM-Cre. Micro-computed tomography of the distal femur of 12-week-old mice revealed a 30% increase in bone volume per total volume of Phlpp1 female conditional knockouts, but we did not observe significant changes within male Phlpp1 cKOLysM mice. Bone histomorphmetry of the proximal tibia further revealed that Phlpp1 cKOLysM females exhibited elevated osteoclast numbers, but conversely had reduced levels of serum markers of bone resorption as compared to littermate controls. Osteoblast number and serum markers of bone formation were unchanged. In vitro assays confirmed that Phlpp1 ablation enhanced osteoclast number and area, but limited bone resorption. Additionally, reconstitution with exogenous Phlpp1 suppressed osteoclast numbers. Dose response assays demonstrated that Phlpp1−/− cells are more responsive to M-CSF, but reconstitution with Phlpp1 abrogated this effect. Furthermore, small molecule-mediated Phlpp inhibition enhanced osteoclast numbers and size. Enhanced phosphorylation of Phlpp substrates—including Akt, ERK1/2, and PKCζ—accompanied these observations. In contrast, actin cytoskeleton disruption occurred within Phlpp inhibitor treated osteoclasts. Moreover, Phlpp inhibition reduced resorption of cells cultured on bovine bone slices in vitro. Our results demonstrate that Phlpp1 deficiency within myeloid lineage cells enhances bone mass by limiting bone resorption while leaving osteoclast numbers intact moreover, we show that Phlpp1 represses osteoclastogenesis and controls responses to M-CSF. |
| Databáze: | OpenAIRE |
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