Fig. 4

Effects of hyperglycemia on osteoblast precursors, primary osteoblasts, and β cells via the non-canonical Wnt pathway

In ST2 cells, BMSCs, hMSCs or MC3T3-E1 cells: hyperglycemia-induced insulin resistance and production of AGEs can directly lead to the activation of NLK, which works in conjunction with the reduction of Wnt ligands, LRP5/6, and FZD4, and increase of Wnt antagonists to inhibit the Wnt/β-catenin pathway. Hyperglycemia-generated ROS can negatively regulate the differentiation process of these cells towards osteoblasts by activating the Ca²⁺/calcineurin/NFATc1 pathway. Hyperglycemia-induced reductions in Wnt3a expression inhibit actin polymerization via the Gα(q/11) (heterotrimeric G protein)/PLC/PKC pathway or JNK pathway, thereby affecting morphological maturation of these cells. In primary osteoblasts: hyperglycemia inhibits the JNK pathway by reducing Wnt16 expression, thereby inhibiting actin polymerization and preventing the binding of c-Jun to transcription factors (e.g. Fosl1 and Fosl2) to inhibit the maturation of primary osteoblasts into mature osteoblasts. In β cells: hyperglycemia-induced increases in Wnt4 levels decrease β cell formation and insulin secretion by activating the JNK pathway in these cells. In MPCs: hyperglycemia-induced increases in Wnt11 promote differentiation of these cells toward adipocytes rather than osteoblasts by activating PKC. Taken together, hyperglycemia can ultimately inhibit bone formation through the above pathways

Abbreviations: hMSCs, human mesenchymal stem cells; MPCs, human bone marrow mesenchymal progenitor cells; Fosl1, recombinant FOS like-antigen 1; Fosl2, recombinant FOS-like antigen 2