ELR+ CXC chemokine signalling in cartilage homeostasis.
The production of ELR+ CXC chemokines is widely studied in arthritis and has been postulated to contribute to the inflammatory phenomena that eventually lead to cartilage breakdown. Healthy articular chondrocytes also express CXC chemokines and chemokine receptors, however their purpose within cartilage is unclear because chondrocytes are encased within a dense avascular extracellular matrix and are not known to migrate in vivo. This study reveals a novel homeostatic function of signalling via CXCR1 and CXCR2 in articular cartilage. Confocal microscopy confirmed the localisation of CXCR1/2 in both in vitro cultured chondrocytes and in human articular cartilage explants at the cell membrane as well as within the cytoplasm, as expected considering the internalisation and recycling of these receptors. Calcium mobilisation assays proved that chondrocyte CXCR1/2 are functional and show a higher redundancy than that found in human neutrophils. Disruption of CXCR1/2 signalling at receptor level or by downstream G-protein inhibition resulted in a reduced extracellular matrix sulphated glycosaminoglycan content, and reduced expression of the cartilage differentiation markers COL2A1, Aggrecan, and SOX9, showing that CXCR1/2 signalling is required for the phenotypic stability of adult articular chondrocytes. In normal cartilage, CXCL6 and CXCL8 are present within the cartilage matrix. CXCL8 is bound to heparan sulphate proteoglycans, whilst CXCL6 is sequestered by an as of yet unidentified alternative matrix interaction, contributing to the determination of the chemokine signalling domain. In vivo analysis of CXCR2 knockout mouse knee joints revealed that mice lacking CXCR2 have significantly thinner epiphyseal growth plates and medial tibial plateaus, suggesting that CXCR signalling may be required in cartilage during periods of high chondrocyte turnover. Pharmacological modulation of the CXCR1/2 signalling pathway may allow for the selective inhibition of catabolic inflammatory responses whilst preserving CXCR1/2 maintained chondrocyte phenotypic homeostasis in articular cartilage.
- Theses