title: Mechanical forces induce changes in VEGF and VEGFR-1/sFlt-1 expression in human chondrocytes.
abstract: Expression of the pro-angiogenic vascular endothelial growth factor (VEGF) stimulates angiogenesis and correlates with the progression of osteoarthritis. Mechanical joint loading seems to contribute to this cartilage pathology. Cyclic equibiaxial strains of 1% to 16% for 12 h, respectively, induced expression of VEGF in human chondrocytes dose- and frequency-dependently. Stretch-mediated VEGF induction was more prominent in the human chondrocyte cell line C-28/I2 than in primary articular chondrocytes. Twelve hours of 8% stretch induced VEGF expression to 175% of unstrained controls for at least 24 h post stretching, in promoter reporter and enzyme-linked immunosorbent assay (ELISA) studies. High affinity soluble VEGF-receptor, sVEGFR-1/sFlt-1 was less stretch-inducible than its ligand, VEGF-A, in these cells. ELISA assays demonstrated, for the first time, a stretch-mediated suppression of sVEGFR-1 secretion 24 h after stretching. Overall, strained chondrocytes activate their VEGF expression, but in contrast, strain appears to suppress the secretion of the major VEGF decoy receptor (sVEGFR-1/sFlt-1). The latter may deplete a biologically relevant feedback regulation to inhibit destructive angiogenesis in articular cartilage. Our data suggest that mechanical stretch can induce morphological changes in human chondrocytes in vitro. More importantly, it induces disturbed VEGF signaling, providing a molecular mechanism for a stress-induced increase in angiogenesis in cartilage pathologies.
authors.affiliation: Department of Anatomy and Cell Biology, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, 52074 Aachen, Germany. rbeckmann@ukaachen.de.
authors.forename: Rainer
authors.initials: R
authors.lastname: Beckmann
authors.affiliation: Department of Anatomy and Cell Biology, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, 52074 Aachen, Germany. astrid.houben@ukmuenster.de.
authors.forename: Astrid
authors.initials: A
authors.lastname: Houben
authors.affiliation: Department of Anatomy and Cell Biology, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, 52074 Aachen, Germany. mtohidnezhad@ukaachen.de.
authors.forename: Mersedeh
authors.initials: M
authors.lastname: Tohidnezhad
authors.affiliation: Department of Anatomy and Cell Biology, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, 52074 Aachen, Germany. nkweider@ukaachen.de.
authors.forename: Nisreen
authors.initials: N
authors.lastname: Kweider
authors.affiliation: Department of Anatomy and Cell Biology, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, 52074 Aachen, Germany. afragoulis@ukaachen.de.
authors.forename: Athanassios
authors.initials: A
authors.lastname: Fragoulis
authors.affiliation: Department of Anatomy and Cell Biology, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, 52074 Aachen, Germany. cwruck@ukaachen.de.
authors.forename: Christoph J
authors.initials: CJ
authors.lastname: Wruck
authors.affiliation: Department of Anatomy and Cell Biology, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, 52074 Aachen, Germany. lbrandenburg@ukaachen.de.
authors.forename: Lars O
authors.initials: LO
authors.lastname: Brandenburg
authors.affiliation: Department of Pathology, RWTH Aachen University, 52074 Aachen, Germany. bhermanns@ukaachen.de.
authors.forename: Benita
authors.initials: B
authors.lastname: Hermanns-Sachweh
authors.affiliation: Research Division, Hospital for Special Surgery, Weill Cornell Medical College, New York, NY 10021, USA. goldringm@hss.edu.
authors.forename: Mary B
authors.initials: MB
authors.lastname: Goldring
authors.affiliation: Department of Anatomy and Cell Biology, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, 52074 Aachen, Germany. tpufe@ukaachen.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Pufe
authors.affiliation: Department of Orthopaedic Surgery, RWTH Aachen University, 52074 Aachen, Germany. hjahr@ukaachen.de.
authors.forename: Holger
authors.initials: H
authors.lastname: Jahr
mesh_terms: D002358:Cartilage, Articular / Q000166:cytology; D002460:Cell Line; D048430:Cell Shape; D002478:Cells, Cultured; D019902:Chondrocytes / Q000378:metabolism* / Q000648:ultrastructure; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006801:Humans; D066298:In Vitro Techniques; D008855:Microscopy, Electron, Scanning; D061251:Primary Cell Culture; D011401:Promoter Regions, Genetic; D013314:Stress, Mechanical; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis* / Q000235:genetics; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1