Tenascin-C: A potential driving factor of organ fibrosis

Fibrosis (thickening and scarring of connective tissue) is often the fundamental reason of morbidity and mortality in systemic scleroderma (SSc), however there is no effective therapy to prevent this process. Fibrosis is initiated by molecules called fibroblasts. The triggers initiating fibroblast activation are known, but the factors which keep fibroblasts active are not.

Previous observations have shown that levels of a molecule called TLR4 and of a group of proteins that activate TLR4 are persistently elevated in the skin of SSc patients; the activation of TLR4 by these proteins causes signalling which sustains fibrosis. Prior studies examining fibrosis in SSc patients show that tenascin-C is one of the main proteins that activate TLR4, and that it potentially plays a role in SSc by contributing to the persistence of skin and lung fibrosis. It is normally under tight regulation, with prominent expression during foetal development but is barely present in healthy adults, except when temporarily expressed during wound healing. Informed by this, Swati Bhattacharyya and her team at the Feinberg School of Medicine at Northwestern University focussed on tenascin-C's expression, mechanism of action and role to evaluate how it may contribute to fibrosis.

The levels of tenascin-C were found to be significantly higher in the skin samples of SSc patients compared to healthy controls. Samples from healthy controls showed barely detectable levels of protein accumulation in the skin, whereas it was readily detectable in SSc patients. The levels of circulating tenascin-C throughout the body was also higher in SSc patients compared to healthy controls. These results therefore indicate, for the first time, that in SSc patients, tenascin-C levels are elevated in the skin and in circulation.

To investigate if tenascin-C had any fibrotic effect, the team tested fibroblast activity in the presence tenascin-C in comparison to fibroblasts in the absence of tenascin-C. The test showed that in the presence of tenascin-C, there was an increased rate of fibroblast movement, helping to explain why there was increased wound healing. This provides evidence for the theory that tenascin-C encourages the activity of fibroblasts.

The results from the study are very exciting, as they indicate that it may be possible to selectively target the generation and accumulation of tenascin-C, or their recognition by TLR4, to limit their fibrotic activity. Novel drugs developed from this information would be of huge benefit to those suffering from SSc, as they may help to relieve some of the debilitating symptoms suffered and in doing so, greatly improve the quality of life for some of our community members.