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

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 b-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. ß

Update on Bone Anabolics in Osteoporosis Treatment: Rationale, Current Status, and Perspectives

“…Another study demonstrated the abrogation of glucocorticoid-induced bone loss by the GSK3␤ inhibitor 6-bromoindirubin-3Ј-oxim (77). Furthermore, the novel GSK3␤ inhibitor AR28 induced ␤-catenin nuclear translocation and increased bone mass after 2 wk, possibly due to an amplification of mesenchymal stem cells that became osteoblasts at the expense of adipocytes (78).…”

Puerarin stimulates osteoblasts differentiation and bone formation through estrogen receptor, p38 MAPK, and Wnt/β-catenin pathways

“…In vitro deletion of the b-catenin gene significantly reversed the increased ALP activity observed in Axis inhibition protein 2 knockout bone marrow stromal cells [20]. Whereas induced b-catenin nuclear translocation was shown to enhance bone mass in BALB/c mice [21]. Furthermore, inhibition of p38 MAPK could interrupt canonical Wnt/b-catenin signaling, and attenuate the Wnt3a-induced b-catenin accumulation [22].…”

Progeroid syndromes: models for stem cell aging?

“…Progeroid syndromes and particularly DS are an invaluable model to determine the molecular markers predisposing to stem cell aging and are suitable to unveil new molecular targets for chemical intervention. Identification of compounds which can be used to manipulate stem cells for therapeutic purposes is well underway with proof-ofconcept approaches in small molecule manipulation of both ES cells and adult tissue stem/progenitor cells (Gambardella et al 2011;Sato et al 2004;Chen et al 2006;Trowbridge et al 2006). These early studies points to interesting times for progeroid syndromes, stem cell biology and aging research.…”