The periosteum contains multipotent skeletal progenitors that contribute to bone repair. The signaling pathways regulating the response of periosteal cells to fracture are largely unknown. Phosphatidylinositol-3 Kinase (PI3K), a prominent lipid kinase, is a major signaling protein downstream of several factors that regulate osteoblast differentiation. Cbl is an E3 ubiquitin ligase and a major adaptor protein that binds to the p85 regulatory subunit and modulates PI3K activity. Substitution of tyrosine 737 to phenylalanine (Y737F) in Cbl abolishes the interaction between Cbl and p85 subunit without affecting the Cbl's ubiquitin ligase function. Here, we investigated the role of PI3K signaling during the very early stages of fracture healing using Osterix reporter mice. We found that the absence of PI3K regulation by Cbl resulted in robust periosteal thickening, with increased proliferation of periosteal cells. While the multipotent properties of periosteal progenitors to differentiate into chondrocytes and adipocytes did not change, osteogenic differentiation in the absence of Cbl-PI3K interaction was highly augmented. The increased stability and nuclear localization of Osterix observed in periosteal cells lacking Cbl-PI3K interaction may explain this enhanced osteogenic differentiation since the expression of Osterix transcriptional target genes including osteocalcin and BSP are increased in YF cells. Overall, our findings highlight a hitherto unexplored and novel role for Cbl and PI3K in modulating the osteogenic response of periosteal cells during the early stages of fracture repair.
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http://dx.doi.org/10.1016/j.bone.2016.11.020 | DOI Listing |
J Clin Med
November 2024
Department of Restorative Dentistry, Medical University of Bialystok, 15-089 Białystok, Poland.
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View Article and Find Full Text PDFElife
December 2024
Univ Paris Est Creteil, INSERM, IMRB, Creteil, France.
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View Article and Find Full Text PDFJCI Insight
December 2024
Department of Musculoskeletal Regenerative Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
Glucocorticoid-induced osteoporosis (GIOP) lacks fully effective treatments. This study investigated the role of Piezo1, a mechanosensitive ion channel component 1, in GIOP. We found reduced Piezo1 expression in cortical bone osteocytes from patients with GIOP and a GIOP mouse model.
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View Article and Find Full Text PDFNano Lett
November 2024
National Engineering Research Center for Biomaterials, Department of Biomedical Engineering, Sichuan University, Chengdu 610064, China.
The creation of complex multilayer periosteal graft structures is challenging. This study introduced a novel bottom-up approach to assemble cell-laden nanofiber mats into a three-dimensional (3D) multilayer periosteum mimic, successfully replicating the hierarchical complexity of the natural periosteum. These nanofiber mats, which were fabricated by electrospinning, surface modification, and stimulated body fluid (SBF) immersion, are composed of nanoscale polycaprolactone (PCL) fibers coated with a mineralized collagen layer along the fiber orientation.
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