Two signal pathways out of control

Interaction of biochemical mechanisms in fibrosis

If in the liver, lungs or other organs the formation of connective tissue gets so out of hand that it can no longer function effectively and, finally, fails completely, it often means that more than one of the body’s regulatory circuits is no longer intact. It has now been proved, that if two signal pathways are out of control, they reinforce one another repressing the influence that normally keeps tissue growth in check. Rheumatologists, immunologists, specialists in paediatrics and pathologists from Erlangen University Hospital and Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU) have studied this connection in detail with colleagues from the USA and Switzerland. In an article published on Tuesday 13 March 2012 in the online journal Nature Communications, they show how this can contribute to a severe fibrosis.

External stimuli reach cells through a number of biochemical processes. Together, these are called signalling cascades. But “wrong” signals can also be given, causing abnormal developments to occur instead of using the organism. The transforming growth factor-b (TGF-b) signalling cascade plays a key role in all fibrotic disorders. In some fibrotic disorders, canonical Wnt-signalling cascades also come into play. TGF-b is named after a growth factor; Wnt refers to one of the messengers. As long as no abnormalities occur, important processes take place via these two paths. For example, both are essential for orderly embryonic development.

However, if these signalling cascades remain active constantly and in turn keep other processes in operation permanently, advanced fibrotic disorders develop. TGF-b then prompts the cells in the connective tissue to generate surplus and increasingly damaging new tissue. As the recently published study shows, however, the influence of the uncontrolled cascade goes further. TGF-b inhibits the synthesis of a protein in the body called Dickkopf-1 (Dkk-1), which acts as an antagonist in the Wnt-signal pathway, thus setting limits on signal transmission. If this counterbalance fades, the Wnt-signalling cascade displays a corresponding increase in activity.

This activation of the Wnt-signal pathway has a strongly pro-fibrotic effect. In cultures, cells produce reinforced components such as collagen, which is used to produce connective tissue. A severe and rapidly advancing fibrosis was observed in mice (par. 2). However, in experimental fibrosis models, where the activation of this TGF-b signalling cascade was prevented, then the Wnt-signal pathway also decreased. Conversely, a more active Wnt-cascade increases the pro-disorder effect of TGF-b; if the activation is prevented, the effect drops. This can be seen when synthesis of Dkk-1 is increased. Despite the pathogenic influence of TGF-b, mice with increased Dkk-1 are almost completely protected (par. 3).

Using these results, research scientists from Medical Clinic 3 – Rheumatology and Immunology, the Children and Young People’s Clinic and the Pathological Institute in Erlangen worked in cooperation with the University of Michigan and Zurich University Hospital and have demonstrated the interaction between the two signal pathways in fibroses. “To date there are no effective drug therapies that hinder the accumulation of connective tissue in the affected organ”, explains the initial author of the study, PD Dr. Jörg Distler from Medical Clinic 3. Now they may find starting points for improved treatments.

More information for the media:

uni | media service | research No. 9/2012 on 15.3.2012