Activation and promotion of adipose stem cells by tumour necrosis factor-α preconditioning for bone regeneration

There is a major medical need for developing novel and effective approaches for repairing non-union and critical-sized bone defects. Although the mechanisms remain to be determined, it is known that inflammation plays a crucial role in initiating bone repair and regeneration. This study investigated the effect of short-term (3 days) preconditioning with tumor necrosis factor-alpha (TNF-α) on proliferation, mobilization, and differentiation of adipose tissue-derived mesenchymal stem cells (ASCs). We demonstrated that TNF-α pre-conditioning increased proliferation, mobilization, and osteogenic differentiation of ASCs and up-regulated bone morphogenetic protein-2 (BMP-2) protein level. BMP-2 silencing by siRNA partially inhibited osteogenic differentiation of ASCs induced by TNF-α; BMP-2 pre-conditioning also significantly increased osteogenic differentiation of ASCs but the effects were significantly smaller than those observed for TNF-α preconditioning. Furthermore, TNF-α treatment promoted extracellular-signal-regulated kinases(Erk)1/2 and p38 mitogen-activated protein kinase (MAPK) signaling pathways, but only Erk1/2 inhibition reduced the BMP-2 levels and osteogenic differentiation induced by TNF-α preconditioning. Together, these results support the hypothesis that inflammation contributes to bone regeneration by promoting proliferation, mobilization, and osteogenic differentiation of ASCs; 3 days of TNF-α preconditioning, mimicking the short boost of inflammation normally occurring after bone injury, might serve as a feasible approach for directing stem cells into osteogenic differentiation.