title: Distinct signaling pathways are involved in hypoxia- and IL-1-induced VEGF expression in human articular chondrocytes.
abstract: Recent data suggest that vascular endothelial growth factor (VEGF) is involved in the pathogenesis of osteoarthritis (OA). Cartilage is an avascular tissue, leading to a low cartilage O2 level. Thus, in a variety of pathologic or physiologic conditions, VEGF is partly regulated by hypoxic stress. The implications of hypoxia for VEGF expression by OA chondrocytes, however, are not known. We investigated the regulatory system of VEGF in OA chondrocytes under hypoxic conditions. Chondrocytes were obtained from articular cartilage of patients with OA. Cells were cultured and then incubated under hypoxic (95% N2, 5% CO2) or normoxic conditions, with or without interleukin (IL)-1 (10 ng/mL) stimulation. The mitogen activated protein kinase (MAPK) inhibitors were also used. VEGF levels in the culture supernatants were measured using an enzyme-linked immunosorbent assay. Western blot analysis was used to examine the expression of hypoxia inducible factor (HIF)-1alpha. Hypoxia significantly increased VEGF levels (p<0.05). Hypoxia-induced VEGF secretion was abolished by p38MAPK inhibitor, but not by JNK inhibitor. In contrast, IL-1-induced VEGF secretion was blocked by JNK inhibitor, and not by p38MAPK inhibitor. Both hypoxia and IL-1-induced HIF-1alpha were attenuated by p38 MAPK and JNK inhibitors. We demonstrate that hypoxia and IL-1 induce VEGF production in chondrocytes through distinct MAPK signaling pathways, indicating that VEGF is induced in a HIF-1-dependent or -independent manner in chondrocytes.
authors.affiliation: Institute of Medical Science, St. Marianna University School of Medicine, Kawasaki-city, 2-16-1 Sugao, Miyamae-ku, Kanagawa 216-8512, Japan.
authors.forename: Minako
authors.initials: M
authors.lastname: Murata
authors.forename: Kazuo
authors.initials: K
authors.lastname: Yudoh
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nakamura
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kato
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Inoue
authors.forename: Junji
authors.initials: J
authors.lastname: Chiba
authors.forename: Kusuki
authors.initials: K
authors.lastname: Nishioka
authors.forename: Kayo
authors.initials: K
authors.lastname: Masuko-Hongo
mesh_terms: D000368:Aged; D002358:Cartilage, Articular / Q000166:cytology; D002478:Cells, Cultured; D019902:Chondrocytes / Q000378:metabolism*; D005260:Female; D006801:Humans; D000860:Hypoxia / Q000503:physiopathology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007375:Interleukin-1 / Q000502:physiology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology; D008297:Male; D020370:Osteoarthritis, Knee / Q000378:metabolism*; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007375:Interleukin-1; D042461:Vascular Endothelial Growth Factor A; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases