Recent advances in osteonecrosis of the femoral head: a focus on mesenchymal stem cells and adipocytes.

Osteonecrosis of the femoral head (ONFH) is a debilitating orthopedic disease characterized by femoral head collapse and destruction of bone and articular cartilage, resulting in severe joint pain and loss of hip mobility. Bone marrow mesenchymal stem cells (BMSCs) exhibit multilineage differentiation potential, including osteoblasts, adipocytes, fibroblasts, chondrocytes, and neurocytes. The imbalance between osteogenesis and adipogenesis in BMSCs plays a critical role in ONFH pathogenesis. Factors such as alcohol consumption and glucocorticoid exposure promote adipogenic differentiation while inhibiting osteogenic differentiation, leading to excessive adipocyte accumulation, reduced bone formation, and vascular impairment. We highlight the molecular mechanisms underlying ONFH with a particular focus on the role of BMSCs and further discuss the involvement of adipocytes. Moreover, we suggest that the use of adipose-derived mesenchymal stem cells (ADMSCs) is a viable approach for stem cell therapy and may have immense potential in ONFH. Several signaling pathways, including the Wnt, TGFβ/BMP, and PI3K/AKT pathways, along with various RNAs and other regulators, govern the osteogenesis and adipogenesis of BMSCs. These signaling pathways target essential transcription factors, such as Runx2 for osteogenesis and PPARγ and C/EBPs for adipogenesis. Adipocytes and their secreted adipokines, including leptin and adiponectin, strongly influence ONFH progression. Emerging therapies involving ADMSCs show potential for promoting bone regeneration and neovascularization. Our review provides a comprehensive overview of the current understanding of ONFH mechanisms by focusing on mesenchymal stem cells and adipocytes and suggests future research directions for therapeutic interventions.