Hypoxia-induced production of stromal cell-derived factor 1 (CXCL12) and vascular endothelial growth factor by synovial fibroblasts

Arthritis Rheum. 2002 Oct;46(10):2587-97. doi: 10.1002/art.10520.


Objective: Stromal cell-derived factor 1 (SDF-1; or, CXCL12) is a potent chemotactic and angiogenic factor that has been proposed to play a role in the recruitment of lymphocytes into rheumatoid arthritis (RA) synovium. We tested the hypothesis that synovial SDF-1 expression is regulated by cytokine and hypoxic stimulation, the latter being mediated by hypoxia-inducible factor 1alpha (HIF-1alpha). These factors regulate the expression of vascular endothelial growth factor (VEGF), itself an important angiogenic mediator.

Methods: RA and osteoarthritic synovial fibroblasts and whole tissue explants were cultured under normoxic or hypoxic (1% O(2)) conditions for up to 72 hours in the presence or absence of interleukin-1beta (IL-1beta), tumor necrosis factor (TNF), or transforming growth factor beta (TGFbeta). Expression of HIF-1alpha, VEGF, and SDF-1 was detected in synovial tissue and cells by immunohistochemistry and Western blotting. VEGF and SDF-1 expression by cultured synovial fibroblasts was evaluated by reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay.

Results: Immunohistochemistry revealed the presence of HIF-1alpha, VEGF, and SDF-1 in RA synovium. Patchy expression of HIF-1alpha was detected primarily in the synovial lining and sublining areas; expression in synovial fibroblasts and in the lining cells of whole synovial tissue explants was markedly augmented by hypoxic culture conditions. Hypoxia enhanced the expression of VEGF and SDF-1 messenger RNA in synovial fibroblasts. The production of VEGF and SDF-1 protein by synovial fibroblasts was augmented by 50% and 132%, respectively, after 24 hours of hypoxia. VEGF production was potently induced by TGFbeta, and to a lesser extent by IL-1beta and TNF, and was further augmented by hypoxia. In contrast, none of the tested cytokines induced SDF-1 production.

Conclusion: As with VEGF, SDF-1 expression is induced by hypoxia; however, cytokines induce VEGF but not SDF-1. Hypoxic conditions in RA synovium, which are likely to be transient and episodic, may contribute to the persistence of synovitis by inducing VEGF and SDF-1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Arthritis, Rheumatoid / metabolism*
  • Arthritis, Rheumatoid / pathology
  • Cells, Cultured
  • Chemokine CXCL12
  • Chemokines, CXC / metabolism*
  • Endothelial Growth Factors / metabolism*
  • Fibroblasts / cytology
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism*
  • Humans
  • Hypoxia / metabolism*
  • Hypoxia / pathology
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Interleukin-1 / pharmacology
  • Lymphokines / metabolism*
  • Synovial Membrane / cytology
  • Synovial Membrane / metabolism
  • Transforming Growth Factor beta / pharmacology
  • Tumor Necrosis Factor-alpha / pharmacology
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors


  • Antineoplastic Agents
  • CXCL12 protein, human
  • Chemokine CXCL12
  • Chemokines, CXC
  • Endothelial Growth Factors
  • Intercellular Signaling Peptides and Proteins
  • Interleukin-1
  • Lymphokines
  • Transforming Growth Factor beta
  • Tumor Necrosis Factor-alpha
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors