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

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Abstract
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 α (TNFα), and human and murine vascular markers were examined by immunohistochemistry and doubleimmunofluorescence. 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, TNFα, 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 TNFα. In contrast to TNFα, SDF‐1 did not induce intracellular adhesion molecule 1 in transplant microvasculature. Furthermore, intragraft injection of SDF‐1 did not up‐regulate TNFα, 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 TNFα, 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.