Biomedicines, 22 March 2026
Steroid-induced osteonecrosis of the femoral head (SONFH) is a serious complication commonly observed in patients undergoing long-term glucocorticoid therapy. The disease progresses insidiously but ultimately leads to destruction of bone architecture, impaired mobility, and frequently necessitates total hip arthroplasty. Because current therapeutic approaches mainly focus on symptom control rather than effectively targeting the underlying pathogenic mechanisms, the development of novel biological treatment strategies has become an important research priority.
A recent study published in Biomedicines (2026) evaluated the therapeutic potential of human umbilical cord–derived mesenchymal stem cells (hUC-MSCs) for the treatment of steroid-induced osteonecrosis of the femoral head. The researchers aimed to clarify the roles of microvascular injury and iron-dependent programmed cell death (ferroptosis), two mechanisms considered central to disease initiation and progression.
Study Design
The investigators conducted both in vivo and in vitro experiments.
In a methylprednisolone-induced SANFH rat model, animals were divided into control, disease, and hUC-MSC-treated groups. Bone structure was assessed using micro-computed tomography (Micro-CT), histological staining, and immunohistochemical analysis.
In vitro, bone microvascular endothelial cells were treated with dexamethasone to simulate steroid-induced injury and subsequently co-cultured with hUC-MSCs to evaluate recovery of cellular function, oxidative stress status, and ferroptosis.
Key Findings
Results from the animal model demonstrated that the disease group exhibited severe trabecular bone destruction, formation of bone cavities, and disrupted femoral head architecture. In contrast, treatment with hUC-MSCs markedly improved bone microarchitecture and significantly reduced the incidence of empty lacunae.
Moreover, the expression of angiogenic markers, including CD31 and VEGF, was substantially increased following hUC-MSC treatment, indicating restoration of the microvascular network.
At the cellular level, dexamethasone suppressed endothelial cell proliferation and induced accumulation of oxidative molecules, including reactive oxygen species (ROS), lipid peroxides, and ferrous ions (Fe²⁺). Concurrently, intracellular antioxidant systems such as glutathione (GSH) and glutathione peroxidase 4 (GPX4) were reduced—hallmarks of ferroptosis.
Co-culture with hUC-MSCs significantly enhanced endothelial cell proliferation and migration, restored tube formation capacity, reduced oxidative stress, inhibited ferroptosis, and improved mitochondrial ultrastructure.
Notably, the study identified that glucocorticoids promote phosphorylation of YAP/TAZ through activation of the Hippo signaling pathway, thereby impairing angiogenesis. hUC-MSCs reversed this process by suppressing Hippo–YAP/TAZ activation, ultimately restoring vascular endothelial function.
Scientific Significance
This study provides novel mechanistic evidence demonstrating that hUC-MSCs not only act on bone tissue but also protect the microvascular system through regulation of ferroptosis and modulation of Hippo signaling. These findings support the “angiogenesis–osteogenesis coupling” hypothesis, in which vascular restoration is a prerequisite for effective bone regeneration.
The ability of hUC-MSCs to regulate oxidative stress and maintain endothelial function suggests that human umbilical cord–derived stem cells may represent a promising biological strategy for preventing early progression of osteonecrosis of the femoral head.
Conclusion and Future Perspectives
The findings indicate that hUC-MSCs can inhibit glucocorticoid-induced ferroptosis, promote neovascularization, improve bone microarchitecture, and protect the femoral head through regulation of the Hippo–YAP/TAZ axis.
These results provide a foundation for mechanism-targeted cell therapy development for SANFH, particularly in early disease stages to delay or potentially avoid hip replacement surgery. Future clinical trials will be necessary to confirm the therapeutic efficacy and long-term safety of hUC-MSC therapy in patients.Top of Form
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References
Xing, H., Cai, W., Chen, J., Xu, H., Zhang, Y., Zhong, C., … & Peng, H. (2026). Human Umbilical Cord Mesenchymal Stem Cells Protect Against Steroid-Induced Osteonecrosis of the Femoral Head Through Hippo Pathway. Biomedicines, 14(3), 727.
Source: Biomedicines
