1. Glycogen synthase kinase-3α/β inhibition promotes in vivo amplification of endogenous mesenchymal progenitors with osteogenic and adipogenic potential and their differentiation to the osteogenic lineage.
- Author
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Gambardella A, Nagaraju CK, O'Shea PJ, Mohanty ST, Kottam L, Pilling J, Sullivan M, Djerbi M, Koopmann W, Croucher PI, and Bellantuono I
- Subjects
- Acid Phosphatase metabolism, Adipocytes metabolism, Alkaline Phosphatase metabolism, Animals, Bone Marrow drug effects, Bone Marrow Cells cytology, Bone Marrow Cells drug effects, Calcification, Physiologic drug effects, Cell Count, Cell Differentiation physiology, Cell Line, Cell Nucleus drug effects, Cell Nucleus metabolism, Cell Proliferation drug effects, Colony-Forming Units Assay, Fibroblasts cytology, Gene Expression drug effects, Gene Expression genetics, Glycogen Synthase Kinase 3 beta, Isoenzymes metabolism, Lipoprotein Lipase genetics, Mesenchymal Stem Cells drug effects, Mesenchymal Stem Cells metabolism, Mice, Osteoblasts metabolism, Osteocalcin genetics, Osteoclasts cytology, Osteoclasts metabolism, Osteogenesis drug effects, PPAR gamma genetics, Protein Kinase Inhibitors administration & dosage, Radiography, Tartrate-Resistant Acid Phosphatase, Tibia anatomy & histology, Tibia cytology, Tibia diagnostic imaging, Tibia drug effects, beta Catenin metabolism, Adipocytes cytology, Cell Differentiation drug effects, Glycogen Synthase Kinase 3 antagonists & inhibitors, Mesenchymal Stem Cells cytology, Osteoblasts cytology, Protein Kinase Inhibitors pharmacology
- Abstract
Small molecules are attractive therapeutics to amplify and direct differentiation of stem cells. They also can be used to understand the regulation of their fate by interfering with specific signaling pathways. Mesenchymal stem cells (MSCs) have the potential to proliferate and differentiate into several cell types, including osteoblasts. Activation of canonical Wnt signaling by inhibition of glycogen synthase kinase 3 (GSK-3) has been shown to enhance bone mass, possibly by involving a number of mechanisms ranging from amplification of the mesenchymal stem cell pool to the commitment and differentiation of osteoblasts. Here we have used a highly specific novel inhibitor of GSK-3, AR28, capable of inducing β-catenin nuclear translocation and enhanced bone mass after 14 days of treatment in BALB/c mice. We have shown a temporally regulated increase in the number of colony-forming units-osteoblast (CFU-O) and -adipocyte (CFU-A) but not colony-forming units-fibroblast (CFU-F) in mice treated for 3 days. However, the number of CFU-O and CFU-A returned to normal levels after 14 days of treatment, and the number of CFU-F was decreased significantly. In contrast, the number of osteoblasts increased significantly only after 14 days of treatment, and this was seen together with a significant decrease in bone marrow adiposity. These data suggest that the increased bone mass is the result of an early temporal wave of amplification of a subpopulation of MSCs with both osteogenic and adipogenic potential, which is driven to osteoblast differentiation at the expense of adipogenesis., (Copyright © 2011 American Society for Bone and Mineral Research.)
- Published
- 2011
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