Tauroursodeoxycholic acid induces angiogenic activity in endothelial cells and accelerates bone regeneration.

Abstract

Angiogenesis is a crucial process during bone tissue regeneration. The aim of this study was to investigate the angiogenic activity and the potentiation of bone regeneration via angiogenesis using tauroursodeoxycholic acid (TUDCA) in vitro and in vivo. We investigated the effect of TUDCA on proliferation and angiogenic differentiation in human umbilical vein endothelial cells (HUVECs) and the associated signaling pathway. Proliferation was determined using crystal violet assay. Angiogenic effects were evaluated based on cell migration and tube formation. In order to explore TUDCA-signaling pathways, phosphorylation of mitogen activated protein kinase, protein kinase B (AKT), and endothelial nitric oxide synthase (eNOS) was determined using western blot. Furthermore, in vivo bone formation and angiogenesis were determined using a New Zealand outbred albino rabbit calvarial defect model, while angiogenesis and bone formation were evaluated using micro-CT and histological analysis. Our results show that TUDCA significantly increased cell proliferation. Moreover, TUDCA enhanced cell migration and tube formation in HUVECs. TUDCA increased the phosphorylation of AKT, ERK1/2, c-Jun N-terminal kinase, and eNOS. Specific inhibitors of ERK1/2 (PD98059), JNK (SP600125), and AKT (AKT1/2) inhibited the TUDCA-induced migration and tube formation, while the p38 inhibitor (SB203580) did not. The in vivo study used TUDCA to accelerate new blood vessel formation and promoted bone formation in rabbit calvarial defect model. These results indicate that TUDCA plays a critical role in enhancing the angiogenesis of endothelial cells and in vivo new bone regeneration. The use of TUDCA may contribute to the regeneration of bone tissue by improving angiogenesis.