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

Abbas Jafari , Majken Siersbæk, Li Chen, Diyako Werya Mohamed Qanie, Walid Zaher, Basem Abdallah, Moustapha Kassem

Research output: Contribution to journalJournal articleResearchpeer-review


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

Original languageEnglish
JournalStem Cells
Issue number7
Pages (from-to)2219–2231
Publication statusPublished - Jul 2015


  • Akt signaling
  • Bone formation
  • Human skeletal (mesenchymal) stem cells
  • Kinase inhibitor
  • Osteoblast differentiation
  • Bone and Bones/metabolism
  • Signal Transduction
  • Humans
  • Proto-Oncogene Proteins c-akt/metabolism
  • Mesenchymal Stem Cells/cytology
  • Animals
  • Transfection
  • rhoA GTP-Binding Protein/metabolism
  • Protein Kinases/metabolism
  • Osteoblasts/metabolism
  • Cell Differentiation
  • Mice


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