Cbfβ: A key regulator in skeletal stem cell differentiation, bone development, and disease

The skeletal system comprises closely related yet functionally distinct bone and cartilage tissues, regulated by a complex network of transcriptional factors and signaling molecules. Among these, core-binding factor subunit beta (Cbfβ) emerges as a critical co-transcriptional factor that stabilizes Runx proteins, playing indispensable roles in skeletal development and homeostasis. Emerging evidence from genetic mouse models has highlighted the essential role of Cbfβ in directing the lineage commitment of mesenchymal stem cells (MSCs) and their differentiation into osteoblasts and chondrocytes. Notably, Cbfβ deficiency is strongly associated with severe skeletal dysplasia, affecting both endochondral and intramembranous ossification during embryonic and postnatal development. In this review, we synthesize recent advancements in understanding the structural and molecular functions of Cbfβ, with a particular focus on its interactions with key signaling pathways, including BMP/TGF-β, Wnt/β-catenin, Hippo/YAP, and IHH/PTHrP. These pathways converge on the Cbfβ/RUNX2 complex, which orchestrates a gene expression program essential for osteogenesis, bone formation, and cartilage development. The integration of these signaling networks ensures the precise regulation of skeletal development, remodeling, and repair. Furthermore, the successful local delivery of Cbfβ to address bone abnormalities underscores its potential as a novel therapeutic target for skeletal disorders such as cleidocranial dysplasia, osteoarthritis, and bone metastases. By elucidating the molecular mechanisms underlying Cbfβ function and its interactions with key signaling pathways, these insights not only advance our understanding of skeletal biology but also offer promising avenues for clinical intervention, ultimately improving outcomes for patients with skeletal disorders.