Wnt signaling inhibits osteogenic differentiation of human mesenchymal stem cells

Wnt signaling and skeletal development

“…In contrast to the data in the cell types described above, Wnt3a was reported to have an adverse effect on ALP expression in human mesenchymal stem cell osteogenic cultures [100][101][102] -the earlier the treatment with Wnt3a conditional medium, the stronger the inhibition of mineralization [100]. However, one report showed that addition of Wnt3a in conditional medium to mouse bone marrow stromal cell osteogenic culture led to increased mineralization [77].…”

“…The LiCl dose dependently induced ALP activity (from 0.1 mM to 20 mM) [95] and ALP mRNA expression in C3H10T1/2 [87,93], ST2 [87], and C2C12 [87] cells. However, it was shown that 4 mM LiCl either had no apparent effect on ALP level (4 mM) in human mesenchymal stem cells [102], or reduced the BMP2-induced osteoblast differentiation (in C2C12 cells and human mesenchymal stem cells) [106] and dexamethasone-induced osteoblast differentiation [100]. LiCl is able to stimulate ALP activity in murine embryonic mesenchymal stem cells but not in calvaria cells [56].…”

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

“…(9) Activation of Wnt signaling by lithium chloride, a nonspecific GSK-3 inhibitor, was shown to suppress dexamethasone-induced osteogenesis. (10) However, other studies have reported that canonical Wnt signaling inhibits MSC proliferation. (11) The use of a Dkk1 blocker induced MSCs to reenter the cell cycle through antagonizing canonical Wnt signaling.…”

“…(14) There are a number of possible reasons behind the controversial findings. In vitro studies have used MSC-like cell lines (13)(14)(15) or primary human MSCs isolated and expanded in vitro under different culture conditions, (9,10,12) mostly in the absence of environmental signals. In vivo studies relied on lossand gain-of-function approaches, (13,16) leading to the presence or absence of factors well beyond physiologic levels, or relied on the use of nonselective GSK-3 inhibitors such as lithium chloride.…”

“…In vivo studies relied on lossand gain-of-function approaches, (13,16) leading to the presence or absence of factors well beyond physiologic levels, or relied on the use of nonselective GSK-3 inhibitors such as lithium chloride. (10,16) In this study we hypothesized that activation of canonical Wnt signaling by an inhibitor of GSK-3 promotes in vivo bone formation as a result of expansion of the mesenchymal progenitor cell compartment. To address this hypothesis, we used a novel selective inhibitor of GSK-3a/b, AR28, and studied the effects on proliferation and differentiation of mesenchymal progenitors in vivo.…”