Editorial: Animal Models of Spondyloarthritis: Do They Faithfully Mirror Human Disease?

Bréban, Maxime; Araujo, Luiza M.; Chiocchia, Gilles

doi:10.1002/art.38636

Cited by 22 publications

(22 citation statements)

References 20 publications

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“…Our findings support that the TgA86 model nicely reproduces cardinal features of the axial and peripheral pathology of the human SpA and, notably, we also show that these mice develop progressive systemic bone loss (osteoporosis), indicated by μCT trabecular analysis of the femur, as well as heart valvular dysfunction with both pathologies suggested to be prevalent comorbidities in human SpA patients (7,32,33). Overall, these mice could be an advantageous SpA mouse model as they spontaneously mimic the complexity of human SpA in a tm-TNF-driven manner.…”

Section: Discussionsupporting

confidence: 86%

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

Christodoulou-Vafeiadou¹,

Geka²,

Ntari³

et al. 2020

Preprint

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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. 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 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.

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Section: Discussionsupporting

confidence: 86%

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

Christodoulou-Vafeiadou¹,

Geka²,

Ntari³

et al. 2020

Preprint

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“…Previous studies have reported several murine models that develop spontaneous ankylosis [29]. For example, DBA/1 mice spontaneously develop ankylosing arthropathy in the ankle joints [30-32].…”

Section: Discussionmentioning

confidence: 99%

“…For example, DBA/1 mice spontaneously develop ankylosing arthropathy in the ankle joints [30-32]. However, these mice mainly exhibit fibrous proliferation in enthesis and fibrous ankylosis, without erosion and bone destruction [29]. McH/lpr-RA1 mice show synovitis, pannus formation and ankylosis, resembling spondyloarthritis [12].…”

Section: Discussionmentioning

confidence: 99%

The effect of anti-IL-6 receptor antibody for the treatment of McH-lpr/lpr-RA1 mice that spontaneously developed ankylosing arthritis

Izumiyama

Mori

Takeda³

et al. 2018

Preprint

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Abstract[Background]McH-lpr/lpr-RA1 mice are a new strain of mice which spontaneously develop arthritis in the ankle, leading finally to ankylosis. There is no published data that drug treatment has been trialed on these mice.[Objectives]This study examined the effect of the mouse anti-IL-6 receptor antibody, MR16-1, for the treatment of ankylosis in McH-lpr/lpr-RA1 mice.[Methods]Male McH-lpr/lpr-RA1 mice were randomly divided into control and treatment groups. MR16-1 was administered from 10 weeks of age for the treatment group. Saline was applied for the control group. The drug was administered once a week, at an initial dose of 2 mg, then maintained at 0.5 mg once per week thereafter. The effects were evaluated by the histopathological synovitis score, in vivo imaging using indocyanine green liposomes, and analysis of the gene expression of inflammatory cytokines.[Results]Tissue analyses were carried out at 14, 17 and 20 weeks of age. The synovitis scores of treated groups were significantly lower compared with those of the control group at every age. The kappa coefficient was 0.77. However, progression of ankylosis persisted in the MR16-1 treated group. In vivo imaging using indocyanine green liposomes showed significant decreases in signal intensities of treated groups at week 14, but no significant differences were observed at week 18. Blood serum amyloid A levels in treated groups were significantly lower at 17 weeks of age. The gene expression levels of Tnf and Il17 were also significantly lower in MR16-1 treated groups.[Conclusions]Administration of the anti-IL-6 receptor antibody is effective for the treatment of synovitis and bone destruction of McH-lpr/lpr-RA1 mice. McH-lpr/lpr-RA1 mice may be a suitable experimental model for the development of new treatments for spondyloarthritis. IL6 signal blockade could contribute to the treatment of spondyloarthritis, and further studies should be carried out to confirm its potential in the prevention of deformity associated with ankylosis.

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“…More recently, these pathologies have been uni ed based on common and overlapping features including in ammation of peripheral joints, the spine and/or sacroiliac joints as well as structural damage dominated by bone destruction and progressive bone formation eventually evolving into axial and peripheral joint ankylosis (1,(3)(4)(5). Additional features include extraarticular manifestations such as psoriasis, uveitis, IBD, aortitis and osteoporosis (6,7).…”

Section: Introductionmentioning

confidence: 99%

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

-Vafeiadou

Geka

Ntari

et al. 2020

Preprint

View full text Add to dashboard Cite

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 role of transmembrane TNF in the pathogenic mechanisms of spondyloarthritis and for assessing the efficacy of human therapeutics targeting different phases of the disease.

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Editorial: Animal Models of Spondyloarthritis: Do They Faithfully Mirror Human Disease?

Cited by 22 publications

References 20 publications

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

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

The effect of anti-IL-6 receptor antibody for the treatment of McH-lpr/lpr-RA1 mice that spontaneously developed ankylosing arthritis

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

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