Ectopic bone formation and systemic bone loss in a transmembrane TNF-driven model of human spondyloarthritis
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(2020) 22:232
RESEARCH ARTICLE
Open Access
Ectopic bone formation and systemic bone loss in a transmembrane TNF-driven model of human spondyloarthritis Eleni Christodoulou-Vafeiadou1, Christina Geka1, Lydia Ntari1, Ksanthi Kranidioti1, Eleni Argyropoulou1, Florian Meier2,3, Marietta Armaka4, Iordanis Mourouzis5, Constantinos Pantos5, Maritina Rouchota6, George Loudos6, Maria C. Denis1, Niki Karagianni1 and George Kollias4,7*
Abstract Background: The transmembrane-TNF transgenic mouse, TgA86, has been shown to develop spontaneously peripheral arthritis with signs of axial involvement. To assess similarity to human spondyloarthritis, we performed detailed characterization of the axial, peripheral, and comorbid pathologies of this model. Methods: TgA86 bone pathologies were assessed at different ages using CT imaging of the spine, tail vertebrae, and hind limbs and characterized in detail by histopathological and immunohistochemical analysis. Cardiac function was examined by echocardiography and electrocardiography and bone structural parameters by μCT analysis. The response of TgA86 mice to either early or late anti-TNF treatment was evaluated clinically, histopathologically, and by μCT analysis. Results: TgA86 mice developed with 100% penetrance spontaneous axial and peripheral pathology which progressed with time and manifested as reduced body weight and body length, kyphosis, tail bendings, as well as swollen and distorted hind joints. Whole-body CT analysis at advanced ages revealed bone erosions of sacral and caudal vertebrae as well as of sacroiliac joints and hind limbs and, also, new ectopic bone formation and eventually vertebral fusion. The pathology of these mice highly resembled that of SpA patients, as it evolved through an early inflammatory phase, evident as enthesitis and synovitis in the affected joints, characterized by mesenchymal cell accumulation, and neutrophilic infiltration. Subsequently, regression of inflammation was accompanied by ectopic bone formation, leading to ankylosis. In addition, both systemic bone loss and comorbid heart valve pathology were evident. Importantly, early anti-TNF treatment, similar to clinical treatment protocols, significantly reduced the inflammatory phase of both the axial and peripheral pathology of TgA86 mice. (Continued on next page)
* Correspondence: [email protected] 4 Institute of Immunology, Biomedical Sciences Research Center (BSRC), ‘Alexander Fleming’, 34 Alexander Fleming Street, 16672 Vari, Greece 7 Department of Physiology, School of Medicine, National Kapodistrian University, Athens, Greece Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The imag
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