Thrombin induced by the extrinsic pathway and PAR-1 regulated inflammation at the site of fracture repair.

Sato N, Ichikawa J, Wako M, Ohba T, Saito M, Sato H, Koyama K, Hagino T, Schoenecker JG, Ando T, Haro H
Bone. 2016 83: 23-34

PMID: 26475502 · DOI:10.1016/j.bone.2015.10.005

Thrombin (coagulation factor IIa) is a serine protease encoded by the F2 gene. Pro-thrombin (coagulation factor II) is cut to generate thrombin in the coagulation cascade that results in a reduction of blood loss. Procoagulant states that lead to activation of thrombin are common in bone fracture sites. However, its physiological roles and relationship with osteoblasts in bone fractures are largely unknown. We herein report various effects of thrombin on mouse osteoblastic MC3T3-E1 cells. MC3T3-E1 cells expressed proteinase-activated receptor 1 (PAR1), also known as the coagulation factor II receptor. They also produced monocyte chemoattractant protein (MCP-1), tissue factor (TF), MCSF and IL-6 upon thrombin stimulation through the PI3K-Akt and MEK-Erk1/2 pathways. Furthermore, MCP-1 obtained from thrombin-stimulated MC3T3-E1 cells induced migration by macrophage RAW264 cells. All these effects of thrombin on MC3T3-E1 cells were abolished by the selective non-peptide thrombin receptor inhibitor SCH79797. We also found that thrombin, PAR-1, MCP-1, TF as well as phosphorylated AKT and p42/44 were significantly expressed at the fracture site of mouse femoral bone. Collectively, thrombin/PAR-1 interaction regulated MCP-1, TF, MCSF and IL-6 production by MC3T3-E1 cells. Furthermore, MCP-1 induced RAW264 cell migration. Thrombin may thus be a novel cytokine that regulates several aspects of osteoblast function and fracture healing.

Copyright © 2015 Elsevier Inc. All rights reserved.

MeSH Terms (20)

Animals Cell Movement Chemokine CCL2 Disease Models, Animal Fracture Healing Humans Inflammation Interleukin-6 Male MAP Kinase Signaling System Mice Mice, Inbred C57BL Models, Biological Osteoblasts Phosphatidylinositol 3-Kinases Proto-Oncogene Proteins c-akt RAW 264.7 Cells Receptor, PAR-1 Thrombin Thromboplastin

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