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Title: Characterization of Skeletal Phenotype and Associated Mechanisms With Chronic Intestinal Inflammation in the Winnie Mouse Model of Spontaneous Chronic Colitis.
Austin Authors: Al Saedi, Ahmed;Sharma, Shilpa;Bani Hassan, Ebrahim;Chen, Lulu;Ghasem-Zadeh, Ali ;Hassanzadeganroudsari, Majid;Gooi, Jonathan H;Stavely, Rhian;Eri, Rajaraman;Miao, Dengshun;Nurgali, Kulmira;Duque, Gustavo
Affiliation: Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, VIC, Australia
Department of Pediatric Surgery, Pediatric Surgery Research Laboratories, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
School of Health Sciences, University of Tasmania, Launceston, TAS, Australia
Calcium Research Laboratory, McGill University Health Centre and Department of Medicine, McGill University, Montreal, QC, Canada
Department of Anatomy, Histology and Embryology, Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China
Institute for Health and Sport, Victoria University, Melbourne, VIC, Australia
St. Vincent's Institute of Medical Research, Melbourne, VIC, Australia
Department of Medicine-Western Health, The University of Melbourne, Melbourne, VIC, Australia
Australian Institute for Musculoskeletal Science (AIMSS), Department of Medicine-Western Health, Melbourne, VIC, Australia
Medicine (University of Melbourne)
Issue Date: 2022
Date: 2021-08-04
Publication information: Inflammatory bowel diseases 2022; 28(2): 259-272
Abstract: Osteoporosis is a common extraintestinal manifestation of inflammatory bowel disease (IBD). However, studies have been scarce, mainly because of the lack of an appropriate animal model of colitis-associated bone loss. In this study, we aimed to decipher skeletal manifestations in the Winnie mouse model of spontaneous chronic colitis, which carries a MUC2 gene mutation and closely replicates ulcerative colitis. In our study, Winnie mice, prior to the colitis onset at 6 weeks old and progression at 14 and 24 weeks old, were compared with age-matched C57BL/6 controls. We studied several possible mechanisms involved in colitis-associated bone loss. We assessed for bone quality (eg, microcomputed tomography [micro-CT], static and dynamic histomorphometry, 3-point bending, and ex vivo bone marrow analysis) and associated mechanisms (eg, electrochemical recordings for gut-derived serotonin levels, real-time polymerase chain reaction [qRT-PCR], double immunofluorescence microscopy, intestinal inflammation levels by lipocalin-2 assay, serum levels of calcium, phosphorus, and vitamin D) from Winnie (6-24 weeks) and age-matched C57BL6 mice. Deterioration in trabecular and cortical bone microarchitecture, reductions in bone formation, mineral apposition rate, bone volume/total volume, osteoid volume/bone surface, and bone strength were observed in Winnie mice compared with controls. Decreased osteoblast and increased osteoclast numbers were prominent in Winnie mice compared with controls. Upregulation of 5-HTR1B gene and increased association of FOXO1 with ATF4 complex were identified as associated mechanisms concomitant to overt inflammation and high levels of gut-derived serotonin in 14-week and 24-week Winnie mice. Skeletal phenotype of the Winnie mouse model of spontaneous chronic colitis closely represents manifestations of IBD-associated osteoporosis/osteopenia. The onset and progression of intestinal inflammation are associated with increased gut-derived serotonin level, increased bone resorption, and decreased bone formation.
DOI: 10.1093/ibd/izab174
ORCID: 0000-0002-2597-6929
Journal: Inflammatory Bowel Diseases
PubMed URL: 34347076
Type: Journal Article
Subjects: Winnie mouse model
Inflammatory bowel disease
gut-derived serotonin
Appears in Collections:Journal articles

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