Skeletal Phenotype and Mechanisms of Bone Loss in Winnie Mice as a Model for Inflammatory Bowel Disease

ObjectiveWe aimed to investigate the skeletal phenotype of Winnie mouse model of spontaneous chronic colitis, which carries a mutation in the Muc2 gene and closely replicates IBD symptoms and pathophysiology. These mice have a high level of gut-derived serotonin (GDS), a potent osteoblastogenesis inhibitor. We explored the underlying mechanisms of bone loss associated with chronic intestinal inflammation. DesignWinnie male and female mice prior to colitis onset (6 weeks old) and progression (14 and 24 weeks) were compared to age- and sex-matched C57BL/6 controls. We assessed bone quality (static and dynamic histomorphometry, micro-CT, 3-point bending), intestinal inflammation (lipocalin-2), GDS levels, serum levels of calcium, phosphorus and vitamin D, ex vivo bone marrow analysis and molecular mechanisms inhibiting osteoblastogenesis. ResultsSignificant deterioration in trabecular and cortical microarchitecture, reductions in bone formation, mineral apposition rate, bone volume, osteoid volume and bone strength were observed in Winnie mice compared to C57BL/6 controls. Decreased osteoblast and increased osteoclast numbers were prominent in Winnie mice. We report for the first time that elevated GDS cross-talks with molecular pathways to inhibit bone formation in Winnie mice. Increased expression of 5-HTR1B and FOXO1 mRNAs, dissociation of FOXO1/CREB1 complex and association of FOXO1 with ATF4, promoting the transcriptional activity of FOXO1, results in suppression of osteoblast proliferation in Winnie mice compared to controls. ConclusionThese findings open avenues for the development of targeted therapies for IBD-related bone loss. Significance of this studyO_ST_ABSWhat is already known on this subject?C_ST_ABS- Osteoporosis is a common extraintestinal manifestation of inflammatory bowel disease (IBD). - Currently available treatments are not effective for IBD-associated bone loss. - The mechanisms of bone loss are poorly understood. A major limitation has been the lack of an appropriate animal model for IBD-associated bone loss. What are the new findings?- We report for the first-time the skeletal phenotype in Winnie mouse model of IBD - This study presents a novel mechanism of IBD-associated bone loss, involving elevated gut-derived serotonin crosstalk with molecular pathways inhibiting bone formation. How might it impact on clinical practice in the foreseeable future- These findings open avenues for the development of targeted therapies for IBD-related bone loss.