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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)
 
 
 
 
 

Role of interleukin-8 in PiT-1 expression and CXCR1-mediated inorganic phosphate uptake in chondrocytes.

OBJECTIVE: The proinflammatory chemokine interleukin-8 (IL-8) induces chondrocyte hypertrophy. Moreover, chondrocyte hypertrophy develops in situ in osteoarthritic (OA) articular cartilage and promotes dysregulated matrix repair and calcification. Growth plate chondrocyte hypertrophy is associated with expression of the type III sodium-dependent inorganic phosphate (Pi) cotransporter phosphate transporter/retrovirus receptor 1 (PiT-1). This study was undertaken to test the hypothesis that IL-8 promotes chondrocyte hypertrophy by modulating chondrocyte PiT-1 expression and sodium-dependent Pi uptake, and to assess differential roles in this activity. METHODS: The selective IL-8 receptor CXCR1 and the promiscuous chemokine receptor CXCR2 were used. Human knee OA cartilage, cultured normal bovine knee chondrocytes, and immortalized human articular chondrocytic CH-8 cells were transfected with CXCR1/CXCR2 chimeric receptors in which the 40-amino acid C-terminal cytosolic tail domains were swapped and site mutants of a CXCR1-specific region were generated. RESULTS: Up-regulated PiT-1 expression was detected in OA cartilage. IL-8, but not IL-1 or the CXCR2 ligand growth-related oncogene alpha, induced PiT-1 expression and increased sodium-dependent Pi uptake by >40% in chondrocytes. The sodium/phosphate cotransport inhibitor phosphonoformic acid blocked IL-8-induced chondrocyte hypertrophic differentiation. Signaling mediated by kinase Pyk-2 was essential for IL-8 induction of PitT-1 expression and Pi uptake. Signaling through the TSYT(346-349) region of the CXCR1 cytosolic tail, a region divergent from the CXCR2 cytosolic tail, was essential for IL-8 to induce Pi uptake. CONCLUSION: Our results link low-grade IL-8- mediated cartilaginous inflammation in OA to altered chondrocyte differentiation and disease progression through PiT-1 expression and sodium-dependent Pi uptake mediated by CXCR1 signaling.[1]

References

  1. Role of interleukin-8 in PiT-1 expression and CXCR1-mediated inorganic phosphate uptake in chondrocytes. Cecil, D.L., Rose, D.M., Terkeltaub, R., Liu-Bryan, R. Arthritis Rheum. (2005) [Pubmed]
 
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