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Extracellular matrix in the crosshairs

Crosstalk between cells and the extracellular matrix (ECM) is an important factor during the development of rheumatoid arthritis (RA). In particular, the ECM molecule tenascin-C is expressed at high levels in the synovium in response to stress and injury and is thought to be involved in the pathogenesis of RA. However, attempts to study tenascin-C as a potential therapeutic target have been hampered by a lack of specific antagonists.

In a new study, researchers used phage display technology to generate antibodies that are specific for the fibrinogen-like globe (FBG) domain of tenascin-C, which binds to Toll-like receptor 4 (TLR4) and is essential for it to trigger pro-inflammatory signalling pathways. “We screened these antibodies to find those that were effective in neutralizing FBG binding to and activation of TLR4, but that did not affect activation of TLR4 by pathogenic stimuli such as bacterial lipopolysaccharide (LPS),” explains corresponding author Kim Midwood.

Credit: Jagrutiben Patel/iStock/Getty Images Plus

In cells isolated from the synovium of patients with RA, the new antibodies blocked the release of cytokines upon stimulation with the FBG domain of tenascin-C but did not affect the release of cytokines upon stimulation with LPS, indicating specificity for targeting ‘sterile’ inflammation in synovial cells. “Using our antibodies, we could also see that tenascin-C expression is elevated very early in the development of RA, even before disease diagnosis,” says Midwood.

When administered at the induction of disease in rats with collagen-induced arthritis, the new antibodies did not prevent the development of disease but did reduce the progression and severity of disease, indicating a role for tenascin-C in the persistence of inflammation.

attempts to study tenascin-C as a therapeutic target have been hampered by a lack of specific antagonists

“We think that targeting disease-specific signals from the RA joint microenvironment that drive the chronicity of inflammation could provide an effective way to reduce pathological inflammation while leaving intact physiological host defence mechanisms against infection,” says Midwood. “This selective approach might offer a safer treatment alternative to global immune suppression for people with RA,” she concludes.


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Correspondence to Joanna Collison.

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Collison, J. Extracellular matrix in the crosshairs. Nat Rev Rheumatol 15, 65 (2019).

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