The Fascinating Paradox of Osteoporosis in Axial Spondyloarthropathy

Fitzgerald, Gillian; O’Shea, Finbar

doi:10.3899/jrheum.170051

Cited by 13 publications

(11 citation statements)

References 44 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 [7,35,36]. Overall, these mice could be an advantageous SpA mouse model as they spontaneously mimic the complexity of human SpA in a tmTNF-driven manner.…”

Section: Discussionsupporting

confidence: 85%

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

Christodoulou-Vafeiadou¹,

Geka²,

Ntari³

et al. 2020

Arthritis Res Ther

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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. 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. Conclusions The 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.

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Section: Discussionsupporting

confidence: 85%

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

Christodoulou-Vafeiadou¹,

Geka²,

Ntari³

et al. 2020

Arthritis Res Ther

View full text Add to dashboard Cite

show abstract

“…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: 85%

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.

show abstract

“…Our ndings 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 (7,35,36). 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: 83%

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.

show abstract

The Fascinating Paradox of Osteoporosis in Axial Spondyloarthropathy

Cited by 13 publications

References 44 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

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

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