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

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 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.

Dual Blockade of TNF and IL-17A Inhibits Inflammation and Structural Damage in a Rat Model of Spondyloarthritis

“…These results confirm the findings of the studies on the transmembrane TNF (tmTNF) transgenic mouse model of SpA, in which it has been shown that the overexpression of tmTNF drives osteoproliferative joint inflammation seen in SpA. TNF receptor I signaling is essential for inflammation and TNF receptor II signaling contributes to pathological new bone formation [ 37 , 38 ]. Moreover, anti-TNF treatment with the etanercept in the same mouse model resulted in a reduction in axial and peripheral inflammation and a reduced bone surface roughness at the level of the caudal spine [ 38 ].…”

“…TNF receptor I signaling is essential for inflammation and TNF receptor II signaling contributes to pathological new bone formation [ 37 , 38 ]. Moreover, anti-TNF treatment with the etanercept in the same mouse model resulted in a reduction in axial and peripheral inflammation and a reduced bone surface roughness at the level of the caudal spine [ 38 ]. In the clinic, TNF inhibitors are established in disease management of axSpA with efficacy in reducing inflammation [ 39 , 40 , 41 ].…”

Juvenile Spondyloarthritis: What More Do We Know About HLA-B27, Enthesitis, and New Bone Formation?

“…A series of recent studies using another preclinical mouse model of TNF overexpression have shed light on how the structure of TNF may contribute to SpA pathogenesis ( 52 , 67 ). The TgA86 mice systemically overexpress a mutant murine TNF gene that is defective at the ADAM17 cleavage site, thereby causing a specific increase of transmembrane-bound TNF (tmTNF) but not soluble TNF (sTNF) ( 68 ).…”

“…Indeed, it was found that stromal tmTNF overexpression could drive inflammation, especially at peripheral sites ( 52 ). Moreover, tmTNF-driven inflammation and bone erosion seemed to precede new bone formation, which involved both endochondral and membranous ossification ( 67 ). However, this model lacks extra-articular manifestations of the SpA disease spectrum, which suggests that additional triggers may be required to induce IBD, uveitis, and/or psoriasis in the background of increased susceptibility owing to the tmTNF-sTNF imbalance.…”

“…The HLA-B27 + transgenic arthritic/colitis rat model persistently developed SpA-like features even after the depletion of CD8 + T cells with either anti-CD8α monoclonal antibodies or CD8α knockout ( 86 , 87 ). Many murine models are also capable of phenocopying SpA to varying degrees in the absence of human HLA-B27, notably through the overexpression of human TNF ( 25 , 26 , 34 , 52 , 67 ). IL-23 overexpression alone in an HLA-B27 − background was also sufficient to drive murine SpA-like disease by activating IL-17-producing entheseal resident non-αβ T cells ( 48 ).…”