Open AccessPharmacological Inhibition of Protein Kinase G1 Enhances Bone Formation by Human Skeletal Stem Cells Through Activation of RhoA‐Akt Signaling
Author(s) -
Jafari Abbas,
Siersbaek Majken S.,
Chen Li,
Qanie Diyako,
Zaher Walid,
Abdallah Basem M.,
Kassem Moustapha
Publication year - 2015
Publication title -
stem cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.159
H-Index - 229
eISSN - 1549-4918
pISSN - 1066-5099
DOI - 10.1002/stem.2013
Subject(s) - rhoa , microbiology and biotechnology , protein kinase b , biology , mesenchymal stem cell , kinase , signal transduction , osteoblast , stromal cell , stem cell , pi3k/akt/mtor pathway , cellular differentiation , cancer research , biochemistry , in vitro , gene
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. S tem C ells 2015;33:2219–2231