Characterization of osteoprotegerin-induced signaling in human endothelial cells

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Background and Objectives: Thrombin is a procoagulant and proinflammatory molecule that is also a potential mediator of bone resorption . Osteoprotegerin (OPG) is a key molecule that binds to the receptor-activator of the nuclear factor-κB (NF-κB) ligand (RANKL), and inhibits osteoclast differentiation. This study aimed to evaluate the biological effects of thrombin on OPG production in human dermal microvascular endothelial cells (HMVEC). Materials and Methods: HMVEC were treated with 2.1-11.2 U/mL of thrombin for 18 h. Thrombin-induced OPG production was assessed by enzyme-linked immunosorbent assay (ELISA). Inhibitors were used to investigate the influence of thrombin on OPG production in HMVEC and the thrombin-signaling pathway. Results: Thrombin induced OPG production in HMVEC in a dose-dependent manner. The phosphatidylinositol 3-kinase (PI3K) inhibitor and Src kinase inhibitor exerted an inhibitory effect on thrombin-induced OPG expression. Thrombin-induced OPG production was also inhibited by the protease-activated receptor (PAR)-1 antagonist. Conclusion: Thrombin induces OPG expression in HMVEC, possibly through PAR-1. Thrombin-induced OPG production is regulated by the PI3K and Src pathways. These findings suggest that thrombin may play a significant role in regulating the levels of serum OPG.