title: Activated platelets increase fibrinolysis of mesenchymal progenitor cells.
abstract: Bone regeneration is initiated by the formation of a blood clot. Activated platelets within this fibrin-rich matrix release signaling molecules that can attract mesenchymal progenitor cells. To gain insight into the cellular mechanism by which activated platelets can support the immigration of mesenchymal progenitors, we have tested the hypothesis that platelet-released signaling molecules increase the capacity of bone marrow stromal cells (BMSC) to activate plasminogen. We report herein that platelet-released supernatants (PRS) elevate total urokinase-type plasminogen activator (uPA) and total plasminogen activator inhibitor-1 (PAI-1) levels in BMSC, as assessed by immunoassay. Quantitative polymerase chain reaction showed an upregulation of uPA, uPA receptor, and PAI-1. Zymography and kinetic analysis based on casein hydrolysis revealed enhanced activity of cell-associated uPA upon exposure of BMSC to PRS. Inhibiting c-Jun N-terminal kinase (JNK) and phosphatidylinositol 3-kinase (PI3K) signaling reduced uPA production and decreased plasminogen activation. Corresponding Western blot analysis showed increased phosphorylation of JNK and AKT in BMSC treated with PRS. These results suggest that activated platelets can enhance the plasminogen activation capacity of mesenchymal progenitors through the stimulation of uPA production, requiring JNK and PI3K/AKT signaling. By this mechanism platelets may contribute to the organization of the blood clot during bone regeneration.
authors.affiliation: Department of Oral Surgery, Medical University of Vienna, Währingerstrasse 25a, 1090 Vienna, Austria.
authors.forename: Hermann
authors.initials: H
authors.lastname: Agis
authors.forename: Barbara
authors.initials: B
authors.lastname: Kandler
authors.forename: Michael B
authors.initials: MB
authors.lastname: Fischer
authors.forename: Georg
authors.initials: G
authors.lastname: Watzek
authors.forename: Reinhard
authors.initials: R
authors.lastname: Gruber
mesh_terms: D000328:Adult; D001777:Blood Coagulation / Q000502:physiology; D001792:Blood Platelets / Q000166:cytology* / Q000502:physiology*; D001861:Bone Regeneration / Q000502:physiology*; D002450:Cell Communication / Q000502:physiology; D005342:Fibrinolysis / Q000502:physiology*; D006801:Humans; D066298:In Vitro Techniques; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010958:Plasminogen / Q000235:genetics / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism; D016133:Polymerase Chain Reaction; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D017154:Stromal Cells / Q000166:cytology / Q000502:physiology; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism
chemical_list: D017395:Plasminogen Activator Inhibitor 1; D010958:Plasminogen; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases; D014568:Urokinase-Type Plasminogen Activator