Stromal cell-derived factor 1 (CXCL12) induces monocyte migration into human synovium transplanted onto SCID Mice

Arthritis Rheum. 2002 Mar;46(3):824-36. doi: 10.1002/art.10102.


Objective: The mechanisms by which monocyte/macrophage cells migrate to the joint involve a series of integrated adhesion and signaling events in which chemokines and their receptors are strongly implicated. This study was undertaken to investigate the hypothesis that stromal cell-derived factor 1 (SDF-1), a CXC chemokine (CXCL12), plays a critical role in monocyte/macrophage localization to synovium.

Methods: SDF-1 and CXC receptor 4 (CXCR4) expression in rheumatoid arthritis (RA) and osteoarthritis synovium and graft SDF-1, tumor necrosis factor alpha (TNF alpha), and human and murine vascular markers were examined by immunohistochemistry and double-immunofluorescence. The functional capacity of SDF-1 to modulate monocyte migration into joints was investigated by examining the localization of pro-myelomonocytic U937 cells into synovial tissue transplanted into SCID mice. SDF-1, TNF alpha, or saline was injected into graft sites and response determined by the number of fluorescently labeled U937 cells (injected intravenously) detected in grafts by ultraviolet microscopy.

Results: SDF-1 and CXCR4 were highly expressed in CD68+ cells in the RA synovium. SDF-1 induced U937 cell migration in vitro and in vivo in a dose-dependent manner and, in vivo, SDF-1 was more effective than TNF alpha. In contrast to TNF alpha, SDF-1 did not induce intracellular adhesion molecule 1 in transplant microvasculature. Furthermore, intragraft injection of SDF-1 did not up-regulate TNF alpha, or vice versa.

Conclusion: This study demonstrates, for the first time, that SDF-1 is functional in vivo when injected into synovial grafts. In addition, SDF-1 is more potent than TNF alpha, and its mechanisms of action appear to be autonomous. Therefore, SDF-1 may be an important TNF-independent molecule involved in the migration to and retention of inflammatory effector cells in the joint.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Animals
  • Antigens, CD / metabolism
  • Antigens, Differentiation, Myelomonocytic / metabolism
  • Arthritis, Rheumatoid / metabolism
  • Blood Vessels / metabolism
  • Cell Line
  • Cell Movement / drug effects
  • Cell Movement / physiology
  • Chemokine CXCL12
  • Chemokines, CXC / administration & dosage
  • Chemokines, CXC / pharmacology
  • Chemokines, CXC / physiology*
  • Dose-Response Relationship, Drug
  • Humans
  • Intercellular Adhesion Molecule-1 / metabolism
  • Mice
  • Mice, SCID
  • Microcirculation
  • Middle Aged
  • Monocytes / drug effects
  • Monocytes / physiology*
  • Osteoarthritis / metabolism
  • Receptors, CXCR4 / metabolism
  • Synovial Membrane / blood supply
  • Synovial Membrane / pathology
  • Synovial Membrane / physiopathology*
  • Synovial Membrane / transplantation*
  • Tumor Necrosis Factor-alpha / metabolism
  • Tumor Necrosis Factor-alpha / pharmacology


  • Antigens, CD
  • Antigens, Differentiation, Myelomonocytic
  • CD68 antigen, human
  • CXCL12 protein, human
  • Chemokine CXCL12
  • Chemokines, CXC
  • Cxcl12 protein, mouse
  • Receptors, CXCR4
  • Tumor Necrosis Factor-alpha
  • Intercellular Adhesion Molecule-1