FOXC1 and FOXC2 in Osteogenesis: Emerging roles and therapeutic potential in bone regeneration and remodeling

Bone is a remarkable dynamic tissue, continually undergoing intricate processes of development, repair, and lifelong remodeling, all vital for maintaining skeletal integrity, facilitating injury recovery, and preserving overall health. Mesenchymal stem cells (MSCs) are central to these processes, characterized by their self-renewal capacity, multipotent differentiation (including osteoblasts), and crucial roles in secreting growth factors and remodeling the extracellular matrix. The highly conserved transcription factors FOXC1 and FOXC2 are crucial for correct skeletal development, profoundly influencing both intramembranous and endochondral ossification. Beyond these established developmental functions, recent evidence illuminates their critical emerging roles in actively regulating MSC osteogenic commitment and promoting osteoblastic differentiation, particularly in early cellular stages. FOXC1, for instance, orchestrates the expression of key osteogenic and chondrogenic transcription factors such as SOX9 (vital for endochondral ossification) and MSX2 (paramount in intramembranous bone formation). FOXC2, in turn, significantly contributes to osteoblast maturation through robust activation of the WNT/β-catenin signaling pathway. Furthermore, compelling experimental studies now directly implicate FOXC1 and FOXC2 in adult bone repair, the maintenance of bone mineral density (BMD), and the modulation of joint health. This bridges their developmental significance to substantial therapeutic potential in adult skeletal pathologies. This review comprehensively synthesizes current understanding of the developmental and emerging adult roles of FOXC1 and FOXC2 in bone biology, with a focused exploration of their underlying molecular and cellular mechanisms in osteogenesis. We also critically discuss their promising therapeutic potential in prevalent skeletal conditions such as fractures, osteoporosis, and osteoarthritis, illustrating how insights from embryonic bone formation can directly inform novel strategies for enhancing adult bone regeneration and remodeling.