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

Abstract

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.

Keywords: Adipocyte; Adipokine; Mesenchymal stem cell; Osteonecrosis of the femoral head; Signaling pathways.

Fig. 1

An imbalance between the osteogenic and adipogenic differentiation of BMSCs leads to ONFH. Under physiological conditions, the osteogenic and adipogenic differentiation of BMSCs is in competitive equilibrium. However, factors such as trauma, alcohol, and glucocorticoids directly promote adipogenesis while simultaneously inhibiting osteogenesis in MSCs. This shift toward diminished osteogenic differentiation and increased adipocytic differentiation of BMSCs is a contributing factor to the development of ONFH

Fig. 2

Major signaling pathways and transcription factors in BMSCs. Factors such as alcohol, hormones, or trauma trigger an increase in SAA expression. SAA inhibits the Wnt/β-catenin signaling pathway and activates the downstream PPARγ of the MAPK signaling pathway. Stimulations with GCs and alcohol can directly reduce bone formation by inhibiting the activity of β-catenin by impeding the Wnt signaling pathway. BMP2 can phosphorylate Smad1/5/9 and drive the activation of osteogenesis and angiogenesis while inhibiting adipogenesis. However, Ski, which functions as a negative regulator through interactions with Smad proteins, can promote adipogenic differentiation. The PI3K/AKT pathway, which is influenced by alcohol stimulation, inhibits proliferation and osteogenic differentiation. These signaling pathways target crucial transcription factors such as Runx2 for osteogenesis and PPARγ and C/EBPs for adipogenesis

Fig. 3

Adipocytes emit a variety of adipokines that participate in the process of femoral head necrosis. PAI-1, an essential extravenous factor, is involved in intravenous thrombus formation through paracrine cell-to-cell interactions. Adiponectin has the potential to increase bone mass by suppressing osteoclastogenesis and stimulating osteoblastogenesis. Furthermore, leptin aids in the differentiation of BMSCs into osteoblasts