Ectopic bone formation and systemic bone loss in a transmembrane TNF-driven model of human spondyloarthritis

Arthritis Research & Therapy

George Loudos¹  Maritina Rouchota¹  Lydia Ntari²  Christina Geka²  Eleni Argyropoulou²  Maria C. Denis²  Niki Karagianni²  Eleni Christodoulou-Vafeiadou²  Ksanthi Kranidioti²  Iordanis Mourouzis³  Constantinos Pantos³  Florian Meier⁴  Marietta Armaka⁵  George Kollias⁶ 

[1] BioEmission Technology Solutions (BIOEMTECH), Attica Technology Park N.C.S.R. “DEMOKRITOS”, Athens, Greece;Biomedcode Hellas SA, Vari, Greece;Department of Pharmacology, School of Medicine, National Kapodistrian University, Athens, Greece;Division of Rheumatology, University Hospital Frankfurt, Goethe University, Frankfurt am Main, Germany;Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Project Group Translational Medicine and Pharmacology TMP, Frankfurt am Main, Germany;Institute of Immunology, Biomedical Sciences Research Center (BSRC), ‘Alexander Fleming’, 34 Alexander Fleming Street, 16672, Vari, Greece;Institute of Immunology, Biomedical Sciences Research Center (BSRC), ‘Alexander Fleming’, 34 Alexander Fleming Street, 16672, Vari, Greece;Department of Physiology, School of Medicine, National Kapodistrian University, Athens, Greece;

关键词: Spondyloarthritis;    Ectopic bone formation;    Vertebral fusion;    Ankylosis;    Comorbidities;    Transmembrane TNF;    Anti-TNF treatment;    Inflammation;    Animal disease model;   

DOI  :  10.1186/s13075-020-02327-4

来源: Springer

【 摘 要 】

BackgroundThe 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.MethodsTgA86 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.ResultsTgA86 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.ConclusionsThe TgA86 mice develop a spontaneous peripheral and axial biphasic pathology accompanied by comorbid heart valvular dysfunction and osteoporosis, overall reproducing the progression of pathognomonic features of human spondyloarthritis. Therefore, the TgA86 mouse represents a valuable model for deciphering the role of transmembrane TNF in the pathogenic mechanisms of spondyloarthritis and for assessing the efficacy of human therapeutics targeting different phases of the disease.

【 授权许可】

CC BY