Fibroblasts are polymorphic cells with pleiotropic roles in organ morphogenesis, tissue homeostasis and immune responses. In fibrotic diseases, fibroblasts synthesize abundant amounts of extracellular matrix, which induces scarring and organ failure. By contrast, a hallmark feature of fibroblasts in arthritis is degradation of the extracellular matrix because of the release of metallo-proteinases and degrading enzymes, and subsequent tissue destruction. In connective tissue diseases such as systemic sclerosis, referred to collectively as ‘fibrosis’, excessive activation of connective tissue cells leads to hardening of the tissue and scarring within the affected organ. In principle, these diseases can affect any organ system and very often lead to disruption of organ function. Connective tissue cells play a key role in normal wound healing in healthy individuals. However, if the activation of connective tissue cells cannot be switched off, fibrotic diseases occur, in which an enormous amount of matrix is deposited in the tissue, leading to scarring and dysfunction of the affected tissue. Until now, scientists did not fully understand why repair processes malfunction in fibrotic diseases.
An international team of scientists led by Dr. Andreas Ramming from the Chair of Internal Medicine III at FAU has now been able to decipher a molecular mechanism responsible for the ongoing activation of connective tissue cells. Scientists from Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Department of Medicine – Rheumatology and Immunology, headed by Professor Georg Schett, have now decrypted a molecular network that controls these processes and could in future provide a new way to treat organ scarring. The results show that the protein PU.1 causes pathological deposition of connective tissue. PU.1 is a transcription factor; it binds to the DNA in the connective tissue cells and reprograms them, resulting in a prolonged deposition of tissue components. In experimental studies, the researchers targeted the protein PU.1. In normal wound healing, the formation of PU.1 is inhibited by the body, so that at the end of the normal healing process the connective tissue cells can return to a resting state. Pharmacological and genetic inactivation of PU.1 disrupts the fibrotic network and enables reprogramming of gene expression that lead to resting fibroblasts (a process called quiescence).
This is in line with the very recent results of another team from the Department of Biosystems Science and Engineering, ETH Zurich, in Basel. They discovered a connection with the PU.1 protein and a cytokine response. PU.1 is a known master regulator of blood formation and promotes myeloid differentiation. The team reported that TNF-alpha, a major inflammatory cytokine, can directly and rapidly up-regulate PU.1 protein in haematopoietic stem cells (HSCs) in vitro and in vivo. This means that TNF-alpha in connective tissues (fibroblast-enriched) could be able to enhance scarring by up-regulating PU.1 as a driver transcription factor. Dr. Ramming commented the implications of his data: “We were able to show that PU.1 is activated in various connective tissue diseases in the skin, lungs, liver and kidneys. PU.1 is not the only factor involved in fibrosis, as factors that are involved in the deposition of scar tissue have already been identified in the past. What has been discovered now, however, is that PU.1 plays a central role in a network of proteins controlling this process. PU.1 is like the conductor in an orchestra: if you take it out, the entire concert collapses. This approach has already been tested using an experimental drug, fuelling the hope that clinical trials on inhibiting PU.1 may soon be able to be launched, aimed at treating fibrosis better”.
The scientists have now published their results in the well known journal Nature.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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