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

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

  • Bone. 2016 Feb;83:23-34. doi: 10.1016/j.bone.2015.10.005.
Nobutaka Sato 1,  Jiro Ichikawa 1,  Masanori Wako 1,  Tetsuro Ohba 1,  Masanori Saito 1,  Hironao Sato 1,  Kensuke Koyama 1,  Tetsuo Hagino 2,  Jonathan G Schoenecker 3,  Takashi Ando 4,  Hirotaka Haro 1
Affiliations

Affiliations

  • 1 Department of Orthopaedic Surgery, Faculty of Medicine, University of Yamanashi, 1110 Shimokatou, Chuo, Yamanashi 409-3898, Japan.
  • 2 Department of Orthopaedic Surgery, Faculty of Medicine, University of Yamanashi, 1110 Shimokatou, Chuo, Yamanashi 409-3898, Japan; The Sports Medicine and Knee Center, Kofu National Hospital, 11-35 Tenjincho, Kofu, Yamanashi 400-8533, Japan.
  • 3 Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, 2200 Children's Way, Nashville, TN 37232-9565, United States; Department of Orthopaedics, Vanderbilt University Medical Center, 2200 Children's Way, Nashville, TN 37232-9565, United States; Department of Center for Bone Biology, Vanderbilt University Medical Center, 2200 Children's Way, Nashville, TN 37232-9565, United States; Department of Pharmacology, Vanderbilt University Medical Center, 2200 Children's Way, Nashville, TN 37232-9565, United States; Department of Pediatrics, Vanderbilt University Medical Center, 2200 Children's Way, Nashville, TN 37232-9565, United States.
  • 4 Department of Orthopaedic Surgery, Faculty of Medicine, University of Yamanashi, 1110 Shimokatou, Chuo, Yamanashi 409-3898, Japan. Electronic address: tando@mtg.biglobe.ne.jp.
PMID: 26475502 DOI: 10.1016/j.bone.2015.10.005
Abstract

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.

Keywords

Fracture model; MCP-1; Migration; PAR-1; Thrombin.

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