title: Chondrocyte death induced by pathological concentration of chemokine stromal cell-derived factor-1.
abstract: 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.
  
  
  CONCLUSIONS
  Our findings suggest a novel pathological mechanism by which high concentrations of SDF-1 in SF induce chondrocyte death during OA and RA.
authors.affiliation: Department of Orthopaedics, Brown Medical School-Rhode Island Hospital, Providence, Rhode Island 02903, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Wei
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Sun
authors.forename: Katsuaki
authors.initials: K
authors.lastname: Kanbe
authors.forename: Zhengke
authors.initials: Z
authors.lastname: Wang
authors.forename: Changqi
authors.initials: C
authors.lastname: Sun
authors.forename: Richard
authors.initials: R
authors.lastname: Terek
authors.forename: Qian
authors.initials: Q
authors.lastname: Chen
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D001168:Arthritis / Q000276:immunology* / Q000473:pathology*; D002478:Cells, Cultured; D054377:Chemokine CXCL12; D018925:Chemokines / Q000008:administration & dosage / Q000276:immunology; D019743:Chemokines, CXC / Q000008:administration & dosage* / Q000276:immunology*; D019902:Chondrocytes / Q000187:drug effects / Q000276:immunology* / Q000473:pathology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged
chemical_list: C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D018925:Chemokines; D019743:Chemokines, CXC