The hypoxic synovial environment regulates expression of vascular endothelial growth factor and osteopontin in juvenile idiopathic arthritis

Maria Carla Bosco, Silvana Delfino, Francesca Ferlito, Maura Puppo, Andrea Gregorio, Claudio Gambini, Marco Gattorno, Alberto Martini, Luigi Varesio

Research output: Contribution to journalArticlepeer-review


Objective. Synovial angiogenesis, a critical determinant of juvenile idiopathic arthritis (JIA) pathogenesis, is sustained by various mediators, including vascular endothelial growth factor (VEGF) and osteopontin (OPN). We characterized the contribution of the local hypoxic environment to VEGF and OPN production by monocytic cells recruited to the synovium in JIA. Methods. Paired synovial fluid (SF) and peripheral blood (PB) samples were collected from 20 patients with JIA. Mononuclear cells (MC) were isolated, and monocytic cells were purified by adherence, maintained in a hypoxic environment, or subjected to reoxygenation. VEGF and OPN protein concentrations were tested in SF, plasma, and culture supernatants by ELISA, and mRNA expression was assessed in freshly purified and cultured cells by reverse transcriptase-polymerase chain reaction. Synovial tissue was obtained at synovectomy from 4 patients with JIA, and analyzed by immunohistochemistry for VEGF, OPN, CD68, and hypoxia-inducible factor-1α (HIF-1α). Results. VEGF mRNA expression was increased in SFMC and SF monocytic cells compared to matched PBMC and PB monocytic cells or SF lymphocytes, correlating with significantly higher protein levels in SF relative to plasma samples. Accordingly, OPN mRNA expression in SF monocytic cells was associated with significant increase of SF protein. Immunohistochemistry revealed the presence of both factors in synovial tissues at the level of the lining and sublining layers, which colocalized with intense CD68 and HIF-1α staining, suggesting production by hypoxic synovial monocytic cells. VEGF and OPN expression was abrogated upon SF monocytic cell reoxygenation and maintained by exposure to prolonged hypoxia. Conclusion. Hypoxic synovial monocytic cells are a likely source of VEGF and OPN in JIA. These data point to a role for hypoxia in the perpetuation of synovitis in JIA. The Journal of Rheumatology

Original languageEnglish
Pages (from-to)1318-1329
Number of pages12
JournalJournal of Rheumatology
Issue number6
Publication statusPublished - Jun 2009


  • Environment
  • Hypoxia
  • Juvenile idiopathic arthritis
  • Monocytes
  • Osteopontin
  • Synovial fluid
  • Vascular endothelial growth factor

ASJC Scopus subject areas

  • Rheumatology
  • Immunology
  • Immunology and Allergy


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