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

Ahmed Al Saedi, Shilpa Sharma, Ebrahim Bani Hassan, Lulu Chen, Ali Ghasem-Zadeh, Majid Hassanzadeganroudsari, Jonathan Gooi, Rhian Stavely, Eri Rajamaran, Dengshun Miao, Kulmira Nurgali, Gustavo Duque
2020 bioRxiv   pre-print
Objective: We 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. Design: Winnie male and female mice prior to colitis onset (6 weeks old) and progression
more » ... (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. Results: Significant 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. Conclusion: These findings open avenues for the development of targeted therapies for IBD-related bone loss.
doi:10.1101/2020.09.28.317495 fatcat:wfkvgpylhbcsndmhbn37ln5fpm