Crosstalk between Wnt and bone morphogenetic protein signaling during osteogenic differentiation

Figure 3 Schematic illustration of the crosstalk between the Wnt and bone morphogenetic protein signaling pathways in osteogenesis. A: Binding of Wnt-specific ligand initiates the Wnt signaling pathway. In canonical pathway, activated disheveled 1 protein suppresses glycogen synthase kinase 3 and inhibits β-catenin degradation, thereby increasing the osteogenic gene expression. In non-canonical signaling, both Wnt Ca²⁺-dependent and Wnt planar cell polarity contribute to the upregulation of osteogenic gene expression; B: Bone morphogenetic proteins (BMPs) bind to the heterodimeric type I/II BMP transmembrane serine/threonine kinase receptors and activate the BMP signaling pathway. The canonical pathway becomes active when the BMP ligand binds to its specific receptor, inducing the phosphorylation and binding of receptor-Smads (Smad1/5/8) to the common Smad (Smad4). The translocation of this complex to the nucleus then modulates the expression of BMP target genes and osteogenic differentiation. In non-canonical pathway, activated mitogen-activated protein kinase induces extracellular signal-regulated kinase 1/2 and contributes to the upregulation of Runx2 expression; C: Upregulated Wnt and BMP signaling pathways induce the expression of Runx2/Osterix genes, followed by the expression of osteoblast differentiation genes, resulting in osteogenesis. This involves mesenchymal stem cell differentiation into osteogenic progenitors, pre-osteoblasts, and mature osteoblasts. GSK-3β: Glycogen synthase kinase 3 beta; APC: Adenomatosis polyposis coli; CK1-α: Casein kinase 1 alpha; PKC: Protein kinase C; NFAT: Nuclear factor of activated T cells; Rho: Ras homolog gene family; RAC: Ras-related C3 botulinum toxin substrate; JNK: Jun N-terminal kinase; DVL: Disheveled; TCF/LEF: T-cell factor/lymphoid enhancer-binding factor; MAPK: Mitogen-activated protein kinase; ERK1/2: Extracellular signal-regulated kinase 1/2; MSCs: Mesenchymal stem cells; BMP: Bone morphogenetic protein.