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We read with interest the study by Byrne and colleagues (Gut 2005;54:78–86) outlining the significant therapeutic opportunities provided by manipulation of the RANK/RANK ligand (RANKL)/osteoprotegerin (OPG) system using recombinant Fc-OPG. There are, however, a number of physiological effects of OPG that were not discussed and which demonstrate the depth of influence of the RANK/RANKL/OPG system on both inflammatory disease and possibly immune surveillance mechanisms. These additional actions may provide both novel therapeutic approaches in inflammatory disease and point to other clinical effects of the Fc-OPG construct.
Work published by our own group1 studying the interleukin 2 deficient mouse model of inflammatory bowel and bone disease, using identical doses of Fc-OPG to Byrne et al, demonstrated the effects on gut inflammation, dendritic cell (DC) numbers, and macrophage (Mø) activation, as analysed by both colonic histology and flow cytometry. In the April issue of Gut, Moschen and colleagues (Gut 2005;54:479–487) showed that OPG can be demonstrated on both DC and Møs, also indicating that the molecule has the potential to influence these cells. These observations are in keeping with previous publications which have outlined the role of the RANK/RANKL/OPG system in DC survival, function, and the development of antigen specific memory T cell responses.2 Hence modulation of inflammatory responses in the gut using Fc-OPG could theoretically provide both direct treatment for gut inflammation alongside the associated bone loss described by Bryne et al. OPG has also been shown to influence TRAIL mediated signalling3 which may also impact on the DC microenvironment, preventing DC death, but more significantly has shown effects in prevention of TRAIL induced apoptosis in a number of tumour types.3,4
These findings highlight the fact that OPG can significantly influence survival of different cell types and the full extent of the actions of Fc-OPG in vivo are undoubtedly still yet to be shown.
Conflict of interest: None declared.
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