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bioRxiv · 10.1101/2020.05.14.095588

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

Christodoulou-Vafeiadou, E.·Geka, C.·Ntari, L.·Kranidioti, K.·Argyropoulou, E.·Meier, F.·Armaka, M.·Mourouzis, I.·Pantos, C.·Rouchota, M.·Loudos, G.·Denis, M. C.·Karagianni, N.·Kollias, G.
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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 limps, 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.Conclusions The TgA86 mice develop a spontaneous peripheral and axial biphasic pathology accompanied by comorbid heart valvular dysfunction and osteoporosis, overall faithfully reproducing the progression of pathognomonic features of human spondyloarthritis. Therefore, the TgA86 mouse represents a valuable model for deciphering the pathogenic mechanisms of spondyloarthritis and for assessing the efficacy of human therapeutics targeting different phases of the disease.Competing Interest StatementProf. George Kollias participates in the BoD of Biomedcode; Dr. Florian Meier has received grants from Pfizer. All other authors declare no competing interests.List of abbreviationsASAnkylosing SpondylitisCTComputed TomographyCVDCardiovascular DiseaseEDTAEthylenediaminetetraacetic acidH&EHematoxylin&EosinIBDInflammatory Bowel DiseaseMRIMagnetic Resonance ImagingOPOsteoporosisOPNOsteopontinPsAPsoriatic arthritisRARheumatoid ArthritisReAReactive arthritiss/oSafranin/OSpASpondyloarthritisTgtransgenictmTNFtransmembrane mouseTNF TNF-αTumor Necrosis Factor αTRAPTartrate-resistant acid phosphataseUTRUntranslated RegionwtWild TypeµCTmicro CTView Full Text

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Christodoulou-Vafeiadou, E., Geka, C., Ntari, L., Kranidioti, K., Argyropoulou, E., Meier, F., Armaka, M., Mourouzis, I., Pantos, C., Rouchota, M., Loudos, G., Denis, M. C., Karagianni, N., Kollias, G.. 2020-05-16. Ectopic bone formation and systemic bone loss in a transmembrane TNF-driven model of human spondyloarthritis. https://doi.org/10.1101/2020.05.14.095588

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