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Vascular endothelial growth factor (VEGF) induces matrix metalloproteinase expression in immortalized chondrocytes.
J Pathol 2004; 202(3):367-74JP

Abstract

VEGF (vascular endothelial growth factor), an important angiogenesis factor, appears also to be involved in inflammatory processes. Recent studies have shown that VEGF and its receptors (VEGFR) are expressed on osteoarthritic, but not on normal adult, chondrocytes. To elucidate possible functions of VEGF in osteoarthritic cartilage, the effects of VEGF were studied on immortalized human chondrocytes. Activated matrix metalloproteinase (MMP)-1, MMP-3, MMP-13, tissue inhibitor of metalloproteinases (TIMP)-1, TIMP-2, interleukin (IL)-1beta, IL-6, and tumour necrosis factor-alpha (TNF-alpha) were measured in culture supernatants by enzyme-linked immunosorbent assays, nitric oxide with the Griess reagent, and cell proliferation by [3H]thymidine incorporation. VEGFR-2 mRNA was quantified by real-time reverse transcription-polymerase chain reaction and the protein was identified by immuno-gold electron microscopy. Intracellular signal transduction effects were determined by western blots and electrophoretic mobility shift assays. The chondrocyte cell lines C28/I2, C20/A4, and T/C28a2/a4 expressed functionally active VEGFR-2. VEGF stimulation induced receptor phosphorylation, activation of the mitogen-activated protein kinases ERK 1/2, and long-lasting activation of the transcription factor AP-1 (activator protein-1). VEGF increased secreted MMP-1, MMP-3, and especially MMP-13, which could be effectively reduced by an inhibitor of VEGFR-2 kinase activity. Interestingly, VEGF diminished the expression of TIMP-1 and especially TIMP-2. Under hypoxic conditions, as occur in cartilage, the reduction in TIMP levels was even greater. Furthermore, VEGF induced IL-1beta, IL-6, TNF-alpha, and nitric oxide expression to a small extent and stimulated the proliferation of immortalized chondrocytes. These findings indicate that VEGF is an autocrine stimulator of immortalized chondrocytes that mediates mainly destructive processes in osteoarthritis.

Authors+Show Affiliations

Department of Anatomy, University of Kiel, D-24098 Kiel, Germany.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

14991903

Citation

Pufe, Thomas, et al. "Vascular Endothelial Growth Factor (VEGF) Induces Matrix Metalloproteinase Expression in Immortalized Chondrocytes." The Journal of Pathology, vol. 202, no. 3, 2004, pp. 367-74.
Pufe T, Harde V, Petersen W, et al. Vascular endothelial growth factor (VEGF) induces matrix metalloproteinase expression in immortalized chondrocytes. J Pathol. 2004;202(3):367-74.
Pufe, T., Harde, V., Petersen, W., Goldring, M. B., Tillmann, B., & Mentlein, R. (2004). Vascular endothelial growth factor (VEGF) induces matrix metalloproteinase expression in immortalized chondrocytes. The Journal of Pathology, 202(3), pp. 367-74.
Pufe T, et al. Vascular Endothelial Growth Factor (VEGF) Induces Matrix Metalloproteinase Expression in Immortalized Chondrocytes. J Pathol. 2004;202(3):367-74. PubMed PMID: 14991903.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Vascular endothelial growth factor (VEGF) induces matrix metalloproteinase expression in immortalized chondrocytes. AU - Pufe,Thomas, AU - Harde,Viola, AU - Petersen,Wolf, AU - Goldring,Mary B, AU - Tillmann,Bernhard, AU - Mentlein,Rolf, PY - 2004/3/3/pubmed PY - 2004/4/17/medline PY - 2004/3/3/entrez SP - 367 EP - 74 JF - The Journal of pathology JO - J. Pathol. VL - 202 IS - 3 N2 - VEGF (vascular endothelial growth factor), an important angiogenesis factor, appears also to be involved in inflammatory processes. Recent studies have shown that VEGF and its receptors (VEGFR) are expressed on osteoarthritic, but not on normal adult, chondrocytes. To elucidate possible functions of VEGF in osteoarthritic cartilage, the effects of VEGF were studied on immortalized human chondrocytes. Activated matrix metalloproteinase (MMP)-1, MMP-3, MMP-13, tissue inhibitor of metalloproteinases (TIMP)-1, TIMP-2, interleukin (IL)-1beta, IL-6, and tumour necrosis factor-alpha (TNF-alpha) were measured in culture supernatants by enzyme-linked immunosorbent assays, nitric oxide with the Griess reagent, and cell proliferation by [3H]thymidine incorporation. VEGFR-2 mRNA was quantified by real-time reverse transcription-polymerase chain reaction and the protein was identified by immuno-gold electron microscopy. Intracellular signal transduction effects were determined by western blots and electrophoretic mobility shift assays. The chondrocyte cell lines C28/I2, C20/A4, and T/C28a2/a4 expressed functionally active VEGFR-2. VEGF stimulation induced receptor phosphorylation, activation of the mitogen-activated protein kinases ERK 1/2, and long-lasting activation of the transcription factor AP-1 (activator protein-1). VEGF increased secreted MMP-1, MMP-3, and especially MMP-13, which could be effectively reduced by an inhibitor of VEGFR-2 kinase activity. Interestingly, VEGF diminished the expression of TIMP-1 and especially TIMP-2. Under hypoxic conditions, as occur in cartilage, the reduction in TIMP levels was even greater. Furthermore, VEGF induced IL-1beta, IL-6, TNF-alpha, and nitric oxide expression to a small extent and stimulated the proliferation of immortalized chondrocytes. These findings indicate that VEGF is an autocrine stimulator of immortalized chondrocytes that mediates mainly destructive processes in osteoarthritis. SN - 0022-3417 UR - https://www.unboundmedicine.com/medline/citation/14991903/Vascular_endothelial_growth_factor__VEGF__induces_matrix_metalloproteinase_expression_in_immortalized_chondrocytes_ L2 - https://doi.org/10.1002/path.1527 DB - PRIME DP - Unbound Medicine ER -