Background/Purpose: The morbidity of spondyloarthritis (SpA) is determined not only by inflammation but also by structural damage, in particular osteoproliferation leading to joint ankylosis. The failure of TNF blockers to halt osteoproliferation raised the concept that inflammation and osteoproliferation are uncoupled processes in SpA. The observation that inflammation and osteoproliferation are linked in experimental and human SpA and that NSAID treatment can retard new bone formation, suggest an alternative hypothesis: inflammatory mediators distinct from soluble TNF (sTNF) are responsible for pathologic new bone formation in SpA. Here, we tested this hypothesis by studying inflammation and new bone formation in mice selectively overexpressing membrane-bound TNF (mTNF).

Methods: mTNF mice have normal levels of sTNF and increased levels of mTNF¹. mTNF mice and non-transgenic littermates were clinically studied over time for arthritis and spondylitis development. At 3, 6 and 8 months peripheral and axial joints were collected and analyzed for inflammation and bone- and cartilage destruction by staining with HE and Saffranin-O. Additionally, X-ray images were obtained from 8 months old mice.

Results: All mTNF mice (100%; n>50) spontaneously developed arthritis, visualized by deformation of joints and loss of grip strength, and spondylitis as evidenced by crinkled tails and hunchback formation, starting at 4 weeks of age and progressing over time. Compared to hTNF and TNF^ΔARE mice the severity of this arthritic disease was mild; moreover mTNF mice did not lose weight due to disease and can survive for more than 8 months.

Analysis of 3 months old mice revealed that arthritis was characterized by inflammation of synovial and entheseal tissue, which also invaded cartilage and bone in some animals. The inflammation was dominated by polymorphonuclear cells (PMNs). Interestingly, multinucleated giant cells, or osteoclasts, were not increased in affected compared to healthy joints. Hypertrophic chondrocytes, as marker for osteoproliferation, were observed outside the bone in the connective tissue next to the inflammatory infiltration. In spondylitis, inflammation was found in connective tissue located at the junction of the annulus fibrosus with the vertebral bone. More severe inflammatory infiltrate could also erode the vertebrae. Also, axial inflammation/destruction was predominantly characterized by PMNs and lack of increased numbers of osteoclasts. Hypertrophic chondrocytes were observed at the edge of the vertebral body, in conjunction with the ongoing inflammation. X-ray images from 8 months old mice also revealed bridging of the tail vertebra. These typical SpA-like features were not observed in any of the non-transgenic littermates analyzed.

Conclusion:  Mice selectively overexpressing mTNF develop a SpA-phenotype with axial and peripheral joint involvement. Radiographic and histologic analysis confirmed new bone formation in this model. Based on these results, we conclude that mTNF, as inflammatory mediator, can drive osteoproliferation in experimental SpA.

Reference: Alexopoulou L, et al. Eur J Immunol 1997; 27(10):2588-92.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/membrane-bound-tnf-drives-axial-and-peripheral-inflammation-and-pathologic-new-bone-formation/