Researchers discover chemical messenger that instructs tissue cells to become aggressive

notch-signalling
The findings of the publication identify the chemical messenger that drives the expansion of destructive tissue in joints

A University of Birmingham team involving members of the Rheumatology Research Group (Professor Christopher Buckley, Professor Karim Raza, Dr Adam Croft, Dr Jennifer Marshall and Dr Andrew Filer) have established that a chemical messenger released by blood vessels instructs tissue cells to become aggressive and destroy joints, a classic symptom of rheumatoid arthritis.

Rheumatoid arthritis is a disease in which tissues of the joint become inflamed and swollen. Why synovial tissue – thin connective tissue that makes up the membranes surrounding joints – expands and how this leads to joint damage has remained unclear, despite there being remarkably effective drugs, such as anti-TNF (tumor necrosis factor), that suppress the disease activity.

The findings of the new publication in collaboration with colleagues in Boston USA, identify the chemical messenger that drives the expansion of destructive tissue in joints called NOTCH3, this molecule is being investigated as a target for the potential use of anti-cancer drugs, as it is overexpressed in several types of cancers. It is hoped that it might be possible to repurpose this drug to treat arthritis.

This research continues the studies led from Birmingham and with the same collaborators that were first described last year in Nature (Croft et al.) that fibroblasts, a key type of resident cell in the synovium, became expanded in rheumatoid arthritis.

Professor Buckley, Kennedy Professor of Translational Rheumatology at the University of Birmingham and Oxford, said: “The identification of NOTCH3 as a key regulator of tissue expansion in the joint and our findings that the degree of expansion relates to the degree of new blood vessel formation links the process of inflammation to angiogenesis (new blood vessel formation) and suggests that blocking NOTCH3 might work in human arthritis.

“It was not expected that NOTCH3, which plays an important role in brain development, would play such a key role in arthritis.”

Dr Adam Croft, NIHR Academic Clinical Lecturer in Rheumatology, added: “This study takes us a further step forward to developing therapies that target the bad fibroblasts in inflammatory joint disease.”

The University's Rheumatology Research Group will be further researching what factors lead to the breakdown of the lining layer in the synovium that sits above the expanded cells surrounding the blood vessels.

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