Send letter to journal:
Re: Rank Ligand and Osteoprotegerin; emerging roles in mucosal inflammation

Dear Editor,

We read with interest the manuscript of Byrne et al. published in the January edition of Gut. The manuscript outlined the significant therapeutic opportunities provided by manipulation of the RANK/RANKL/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 group [1] studying the IL2-deficient mouse model of inflammatory bowel and bone disease, using identical doses of Fc- OPG to Byrne et al., demonstrated effects on gut inflammation, dendritic cell (DC) numbers and macrophage (Mø) activation as analysed by both colonic histology and flow cytometry. In the April edition of Gut Moschen et al. highlight that OPG can be demonstrated on both DC and Mø’s, 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 signalling [3] 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 that OPG can significantly influence survival of differing cell types and the full extent of the actions of Fc- OPG in vivo are undoubtedly still yet to be shown.

Authors:
A.J.Ashcroft¹
S.R.Carding².

1 Academic Unit of Haematology and Oncology, School of Medicine.

2 School of Biochemistry and Molecular Biology, University of Leeds, Leeds, UK.

References

1. Ashcroft AJ, Cruickshank SM, Croucher PI, Perry MJ, Rollinson S, Lippitt JM, et al. Colonic dendritic cells, intestinal inflammation, and T cell-mediated bone destruction are modulated by recombinant osteoprotegerin. Immunity 2003;19(6):849-61.

2. Theill LE, Boyle WJ, Penninger JM. RANK-L and RANK: T cells, bone loss, and mammalian evolution. Annu Rev Immunol 2002;20:795-823.

3. Shipman CM, Croucher PI. Osteoprotegerin is a soluble decoy receptor for tumor necrosis factor-related apoptosis-inducing ligand/Apo2 ligand and can function as a paracrine survival factor for human myeloma cells. Cancer Res 2003;63(5):912-6.