Transmembrane TNF drives osteoproliferative joint inflammation reminiscent of human spondyloarthritis

Kaaij, Merlijn H.; Tok, Melissa N. van; Blijdorp, Iris C.; Ambarus, Carmen A.; Stöck, Michael; Pots, Desirée; Knaup, Véronique L.; Armaka, Marietta; Christodoulou-Vafeiadou, Eleni; Melsen, Tessa K. van; Masdar, Huriatul; Eskes, Harry J.P.P.; Yeremenko, Nataliya; Kollias, George; Schett, Georg; Tas, Sander W.; Duivenvoorde, Leonie M. van; Baeten, Dominique

doi:10.1084/jem.20200288

Cited by 28 publications

(51 citation statements)

References 75 publications

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“…5b). Similar structures have been previously reported in human RA patients as well as in TNFdependent mouse models involving bone pathologies [22,23], with no evidence however of a critical contribution of bone marrow cells in the disease pathogenesis [22,24]. Gr1-positive neutrophils were found to accumulate mainly at the sites of the enthesis as well as loosely scattered in the bone marrow cavity and along the periosteum (Fig.…”

Section: New Bone Formation In Tmtnf Transgenic Mice Involves Mechanisupporting

confidence: 84%

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: New Bone Formation In Tmtnf Transgenic Mice Involves Mechanisupporting

confidence: 84%

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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“…Biologically active TNF exists either in a secreted form or as a transmembrane (tm)-bound cytokine, the former being released upon cleavage of the latter by ADAM17 (A disintegrin and metalloproteinase 17, also known as TNF converting enzyme, TACE). In SpA, tmTNF appears to be more expressed in the synovial membrane than in rheumatoid arthritis, and this could be related to lower ADAM17 activity, raising the intriguing possibility that tmTNF could be specially involved in SpA [78]. Indeed, the TgA86 mouse that overexpresses tmTNF -due to defective ADAM17-develops axial and peripheral joint synovitis, enthesitis, and osteitis, with endochondral new bone formation ultimately leading to complete axial and peripheral joint ankylosis, typical of SpA [78,79].…”

Section: B-the Tmtnf-overexpressing Mousementioning

confidence: 99%

“…In SpA, tmTNF appears to be more expressed in the synovial membrane than in rheumatoid arthritis, and this could be related to lower ADAM17 activity, raising the intriguing possibility that tmTNF could be specially involved in SpA [78]. Indeed, the TgA86 mouse that overexpresses tmTNF -due to defective ADAM17-develops axial and peripheral joint synovitis, enthesitis, and osteitis, with endochondral new bone formation ultimately leading to complete axial and peripheral joint ankylosis, typical of SpA [78,79]. In this model, tmTNF expression by stromal cells appears critical, being required for peripheral arthritis and more pathogenic than tmTNF expressed by hematopoietic cells as for spondylitis.…”

Section: B-the Tmtnf-overexpressing Mousementioning

confidence: 99%

Lessons on SpA pathogenesis from animal models

et al. 2021

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Understanding the complex mechanisms underlying a disorder such as spondyloarthritis (SpA) may benefit from studying animal models. Several suitable models have been developed, in particular to investigate the role of genetic factors predisposing to SpA, including HLA-B27, ERAP1 and genes related to the interleukin (IL)-23/IL-17 axis. One of the best examples of such research is the HLA-B27 transgenic rat model that fostered the emergence of original theories regarding HLA-B27 pathogenicity, including dysregulation of innate immunity, contribution of the adaptive immune system to chronic inflammation and influence of the microbiota on disease development. Very recently, a new model of HLA-B27 transgenic Drosophila helped to expand further some of those theories in an unexpected direction involving the TGF/BMP family of mediators. On the other hand, several spontaneous, inducible and/or genetically modified mouse models -including SKG mouse, TNF are mouse and IL-23-inducible mouse model of SpA-have highlighted the importance of TNF and IL-23/IL-17 axis in the development of SpA manifestations. Altogether, those animal models afford not only to study disease mechanism but also to investigate putative therapeutic targets.

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“…MiR-140 was shown to modulate the angiogenesis in hepatocellular carcinoma ( Hou et al, 2020 ). TNF is an important inflammatory factor and involved in inflammation response of multiple organs ( Liu R. et al, 2019 ; Kaaij et al, 2020 ). Our data suggested that deletion of TUG1 relieved LPS-induced hepatocyte inflammation and injury by regulating miR-140/TNF axis both in vivo and in vitro .…”

Section: Discussionmentioning

confidence: 99%

Silencing lncRNA TUG1 Alleviates LPS-Induced Mouse Hepatocyte Inflammation by Targeting miR-140/TNF

Liu

et al. 2021

Front. Cell Dev. Biol.

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Hepatitis is a major public health problem that increases the risk of liver cirrhosis and liver cancer. Numerous studies have revealed that long non-coding RNAs (lncRNAs) exert essential function in the inflammatory response of multiple organs. Herein, we aimed to explore the effect of lncRNA TUG1 in LPS-induced hepatocyte inflammation response and further illuminate the underlying mechanisms. Mice were intraperitoneally injected with LPS, and the liver inflammation was evaluated. Microarray showed that lncRNA TUG1 was upregulated in LPS-induced hepatocyte inflammation. qRT-PCR and immunofluorescence assay indicated a significant increase of TUG1 in mice with LPS injection. Functional analysis showed that si-TUG1 inhibited LPS-induced inflammation response in mice liver, inhibited apoptosis level, and protected liver function. Then, we knock down TUG1 in normal human hepatocyte AML12. Consistent with in vivo results, si-TUG1 removed the injury of LPS on AML12 cells. Furthermore, TUG1 acted as a sponge of miR-140, and miR-140 directly targeted TNFα (TNF). MiR-140 or si-TNF remitted the beneficial effects of TUG1 on LPS-induced hepatocyte inflammation response both in vitro and in vivo. Our data revealed that deletion of TUG1 protected against LPS-induced hepatocyte inflammation via regulating miR-140/TNF, which might provide new insight for hepatitis treatment.

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Transmembrane TNF drives osteoproliferative joint inflammation reminiscent of human spondyloarthritis

Cited by 28 publications

References 75 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

Lessons on SpA pathogenesis from animal models

Silencing lncRNA TUG1 Alleviates LPS-Induced Mouse Hepatocyte Inflammation by Targeting miR-140/TNF

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