Hepatocyte growth factor improves bone regeneration via the bone morphogenetic protein-2-mediated NF-κB signaling pathway

Abstract

Bone regeneration is an important process associated with the treatment of osteonecrosis, which is caused by various factors. Hepatocyte growth factor (HGF) is an active biological factor that has multifunctional roles in cell biology, life sciences and clinical medicine. It has previously been suggested that bone morphogenetic protein (BMP)-2 exerts beneficial roles in bone formation, repair and angiogenesis in the femoral head. The present study aimed to investigate the benefits and molecular mechanisms of HGF in bone regeneration. The viability of osteoblasts and osteoclasts were studied in vitro. In addition, the expression levels of tumor necrosis factor (TNF)-α, monocyte chemotactic protein (MCP)-1, interleukin (IL)-1 and IL-6 were detected in a mouse fracture model following treatment with HGF. The expression and activity of nuclear factor (NF)-κB were also analyzed in osteocytes post-treatment with HGF. Histological analysis was used to determine the therapeutic effects of HGF on mice with fractures. The migration and differentiation of osteoblasts and osteoclasts were investigated in HGF-incubated cells. Furthermore, angiogenesis and BMP-2 expression were analyzed in the mouse fracture model post-treatment with HGF. The results indicated that HGF regulates the cell viability of osteoblasts and osteoclasts, and also balanced the ratio between osteoblasts and osteoclasts. In addition, HGF decreased the serum expression levels of TNF-α, MCP-1, IL-1 and IL-6 in experimental mice. The results of a mechanistic analysis demonstrated that HGF upregulated p65, IκB kinase-β and IκBα expression in osteoblasts from experimental mice. In addition, the expression levels of vascular endothelial growth factor, BMP-2 receptor, receptor activator of NF-κB ligand and macrophage colony-stimulating factor were upregulated by HGF, which may effectively promote blood vessel regeneration, and contribute to the formation and revascularization of tissue-engineered bone. Furthermore, HGF promoted BMP-2 expression and enhanced angiogenesis at the fracture location. These results suggested that HGF treatment may significantly promote bone regeneration in a mouse fracture model. In conclusion, these results indicated that HGF is involved in bone regeneration, angiogenesis and the balance between osteoblasts and osteoclasts, thus suggesting that HGF may be considered a potential agent for the treatment of fractures via the promotion of bone regeneration through regulation of the BMP-2-mediated NF-κB signaling pathway.