PT - JOURNAL ARTICLE AU - Lei Wei AU - Xiaojuan Sun AU - Katsuaki Kanbe AU - Zhengke Wang AU - Changqi Sun AU - Richard Terek AU - Qian Chen TI - Chondrocyte death induced by pathological concentration of chemokine stromal cell-derived factor-1. DP - 2006 Sep 01 TA - The Journal of Rheumatology PG - 1818--1826 VI - 33 IP - 9 4099 - http://www.jrheum.org/content/33/9/1818.short 4100 - http://www.jrheum.org/content/33/9/1818.full SO - J Rheumatol2006 Sep 01; 33 AB - OBJECTIVE: It had been found that the concentration of chemokine stromal cell-derived factor-1 (SDF-1) was significantly higher in synovial fluid (SF) of patients with osteoarthritis (OA; > or = 200 ng/ml) and rheumatoid arthritis (RA; > or = 700 ng/ml) compared to controls (< or = 100 ng/ml). Our aim was to determine whether the pathological concentration of SDF-1 induces chondrocyte death and to investigate mechanisms underlying such death. METHODS: Human OA chondrocytes were treated with different doses of SDF-1, or in combination with SF from patients with arthritis. Apoptotic and necrotic cells were labeled by annexin V and propidium iodide, respectively, and quantified by FACS analysis. Caspase-3 activity was quantified by a plate absorbance assay, and matrix metalloproteinase 13 mRNA levels were determined by RT-PCR. The release of high mobility group box chromatin protein 1, a specific marker of cell necrosis, and the activities of chondrocyte mitogen-activated protein kinases (MAPK) including ERK, JNK, and p38 in response to SDF-1 treatment were quantified by Western blot analysis. RESULTS: Pathological concentrations of SDF-1 (> or = 200 ng/ml) in SF or in recombinant form induced death of human chondrocytes in a necrosis-dependent manner. Chondrocyte death was inhibited by the treatment of cells with anti-CXCR4, an antibody blocking the interaction between SDF-1 and its receptor CXCR4. However, the rate of chondrocyte apoptosis and the level of caspase-3, a key apoptotic enzyme, were not affected by the treatment with anti-CXCR4. SDF-1 stimulated p38 MAPK activity in a dose- and time-dependent manner. The presence of the p38 MAPK inhibitor SB203580 during SDF-1 treatment abolished the induction of chondrocyte death by SDF-1. CONCLUSION: Our findings suggest a novel pathological mechanism by which high concentrations of SDF-1 in SF induce chondrocyte death during OA and RA.