Fig. 2

Signalling pathways that regulate osteoblastogenesis. Osteoblastogenesis is tightly controlled by numerous signaling pathways that regulate the activity of key osteogenic transcription factors, such as Runt-related transcription factor 2 (RUNX2), which are essential for bone regeneration and remodeling. Signaling pathways, including Hippo, Notch, Bone Morphogenetic Protein (BMP), Wnt, Hedgehog, and Fibroblast Growth Factors (FGFs), play a distinct role in regulating osteogenesis, by either promoting or inhibiting the expression of the gene coding for RUNX2. The canonical Wnt/β-catenin pathway is one of the most well-known pathways that positively regulates osteogenesis. Upon binding of Wnt ligands to their receptors (WNTr), β-catenin is stabilized, preventing its degradation. This stabilization allows β-catenin to accumulate in the nucleus, where it promotes the transcription of genes involved in osteoblast differentiation, including RUNX2. Identical outcomes occur when BMP or FGFs bind to their receptors (BMPr and FGFr, respectively), activating the transcription of the messenger RNA coding for RUNX2. Similarly, Hedgehog signaling, modulated by the Smoothened (Smo) and Patched1 (PTCH1) receptors, also supports RUNX2 activity. Hedgehog signaling is crucial not only for osteoblast differentiation but also for the regulation of bone development and tissue maintenance. It interacts with various cellular processes to ensure that osteoblast differentiation occurs properly during skeletal development. On the other hand, Notch signaling exerts a negative regulatory effect on osteogenesis. Upon ligand activation, the Notch receptor interacts with the transcription factor Hey1, which inhibits RUNX2 activity and thus affects both cell differentiation and bone remodeling. This impact of this pathway in bone biology underscores its importance in regulating the balance between osteoblast and osteoclast activity, ensuring proper bone turnover. Another pathway that influences osteoblast differentiation is the Hippo signaling pathway. This pathway regulates cell proliferation and survival. It can negatively impact osteolastogenesis by inhibiting the Yes-associated protein (YAP) and the transcriptional co-activator with PDZ-binding motif (TAZ). When the Hippo pathway is activated, the YAP/TAZ protein pair remains inactive in the cytoplasm, thus preventing osteoblast differentiation. In contrast, when the extracellular matrix (ECM) stiffness increases, integrins cluster and induce the formation of F-actin stress fibers, leading to the translocation of YAP/TAZ into the nucleus (represented as a green dashed line), where they activate the expression of genes associated with osteoblast differentiation, such as RUNX2. The mechanical properties of the ECM (particularly its stiffness) play a crucial role in regulating YAP/TAZ activity. In contrast with a stiff ECM, a softer ECM inhibits the activation of YAP/TAZ, thus preventing osteoblast differentiation. This mechanosensitive regulation highlights the importance of biomechanical forces in the fine-tuning of osteoblastogenesis, a critical step in bone remodeling and regeneration