Pharmacological Inhibition of Protein Kinase G1 Enhances Bone Formation by Human Skeletal Stem Cells Through Activation of RhoA‐Akt Signaling

Development of novel approaches to enhance bone regeneration is needed for efficient treatment of bone defects. Protein kinases play a key role in regulation of intracellular signal transduction pathways, and pharmacological targeting of protein kinases has led to development of novel treatments for...

Full description

Saved in:
Bibliographic Details
Published in:Stem cells (Dayton, Ohio) Ohio), 2015-07, Vol.33 (7), p.2219-2231
Main Authors: Jafari, Abbas, Siersbaek, Majken S., Chen, Li, Qanie, Diyako, Zaher, Walid, Abdallah, Basem M., Kassem, Moustapha
Format: Article
Language:English
Subjects:
Akt signaling
Animals
Bone and Bones - metabolism
Bone formation
Cell Differentiation
Human skeletal (mesenchymal) stem cells
Humans
Kinase inhibitor
Kinases
Mesenchymal Stromal Cells - cytology
Mesenchymal Stromal Cells - metabolism
Mice
Osteoblast differentiation
Osteoblasts - metabolism
Protein Kinases - metabolism
Protein Kinases - pharmacology
Proteins
Proto-Oncogene Proteins c-akt - metabolism
rhoA GTP-Binding Protein - metabolism
Signal Transduction
Stem cells
Transfection
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Development of novel approaches to enhance bone regeneration is needed for efficient treatment of bone defects. Protein kinases play a key role in regulation of intracellular signal transduction pathways, and pharmacological targeting of protein kinases has led to development of novel treatments for several malignant and nonmalignant conditions. We screened a library of kinase inhibitors to identify small molecules that enhance bone formation by human skeletal (stromal or mesenchymal) stem cells (hMSC). We identified H‐8 (known to inhibit protein kinases A, C, and G) as a potent enhancer of ex vivo osteoblast (OB) differentiation of hMSC, in a stage‐ and cell type‐specific manner, without affecting adipogenesis or osteoclastogenesis. Furthermore, we showed that systemic administration of H‐8 enhances in vivo bone formation by hMSC, using a preclinical ectopic bone formation model in mice. Using functional screening of known H‐8 targets, we demonstrated that inhibition of protein kinase G1 (PRKG1) and consequent activation of RhoA‐Akt signaling is the main mechanism through which H‐8 enhances osteogenesis. Our studies revealed PRKG1 as a novel negative regulator of OB differentiation and suggest that pharmacological inhibition of PRKG1 in hMSC implanted at the site of bone defect can enhance bone regeneration. Stem Cells 2015;33:2219–2231
ISSN:1066-5099
1549-4918
DOI:10.1002/stem.2013