INFLAMMATORY BOWEL DISEASE

CD4⁺CD45RB^Hi T cell transfer induced colitis in mice is accompanied by osteopenia which is treatable with recombinant human osteoprotegerin

F R Byrne¹, S Morony², K Warmington², Z Geng², H L Brown¹, S A Flores¹, M Fiorino¹, S L Yin¹, D Hill², V Porkess², D Duryea³, J K Pretorius³, S Adamu³, R Manuokian⁴, D M Danilenko³, I Sarosi³, D L Lacey³, P J Kostenuik², G Senaldi¹

¹ Department of Inflammation, Amgen Inc., Thousand Oaks, California, USA
² Department of Metabolic Disorders, Amgen Inc., Thousand Oaks, California, USA
³ Department of Pathology, Amgen Inc., Thousand Oaks, California, USA
⁴ Department of Pre-clinical and Protein Therapeutics, Amgen Inc., Thousand Oaks, California, USA

Correspondence to:
Correspondence to:
Dr F Byrne
Amgen Inc, One Amgen Center Drive, Mail Stop 29-1-B, Thousand Oaks, California 91320, USA; fbyrne{at}amgen.com

Background and aims: Transfer of CD4⁺CD45RB^Hi T cells into semi syngeneic immunodeficient mice represents a model of inflammatory bowel disease (IBD). As patients with IBD often suffer from osteopenia, we studied if this T cell transfer in mice results in osteopenia in addition to colitis, and if treatment with osteoprotegerin (OPG) has effects on the bone mineral density of T cell transferred mice. We also investigated whether osteopenia was due to malabsorption as a result of a dysregulated digestive tract or as a consequence of the inflammatory process.

Methods: CD4⁺CD45RB^Hi or CD4⁺CD45RB^Lo T cells (4x10⁵) were sorted from CB6F1 and transferred into C.B.17 scid/scid mice. Recipient mice were treated with human IgG1 Fc (control) or Fc-OPG three times per week in a prophylactic regimen as well as a therapeutic regimen (after 10% body weight loss) and were evaluated for osteopenia and colitis.

Results: Mice that received CD4⁺CD45RB^Hi T cells developed osteopenia (as indicated by decreased bone density accompanied by decreased osteoblasts and increased osteoclasts) and colitis (as indicated by histological changes in the large intestine). Mice that received CD4⁺CD45RB^Lo T cells developed neither osteopenia nor colitis. All animals consumed, on average, the same amount of food and water over the course of the study. Prophylactic treatment with Fc-OPG increased bone density in mice that received either CD4⁺CD45RB^Hi or CD4⁺CD45RB^Lo T cells but had no effects on the gastrointestinal tract. Fc-OPG treatment of osteopenic mice with established IBD caused the normalisation of bone density. Osteopenia in CD4⁺CD45RB^Hi T cell recipients was accompanied by hypoparathyroidism that was partially normalised by treatment with Fc-OPG. CD4⁺CD45RB^Hi T cell recipients also had a bone marrow inflammatory cell infiltrate expressing tumour necrosis factor which was unaffected by treatment with Fc-OPG.

Conclusions: CD4⁺CD45RB^Hi T cell transfer results in osteopenia in addition to colitis. Evidence suggests that this osteopenia was induced by inflammatory cell infiltration and not by malabsorption of calcium. Recombinant human osteoprotegerin effectively treated the osteopenia. OPG may be a useful therapeutic option for treating osteopenia in patients with IBD.

Abbreviations: ALP, alkaline phosphatase; BMD, bone mineral density; IBD, inflammatory bowel disease; OPG, osteoprotegerin; PTH, parathyroid hormone; pQCT, peripheral quantitative computer tomography; RANK(L), receptor activator of nuclear factor B (ligand); SAA, serum amyloid A; TRAP, tartarate resistant acid phosphatase; TNF-, tumour necrosis factor

Keywords: inflammatory bowel disease; bone; osteoporosis; osteoprotegerin

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