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Systems Genetics in Inflammatory Disease: From Basic Research to Potential Therapeutic Targets

 14 August 2014   Research News

Enrico_News_hiresMRC researchers uncover druggable gene targets for arthritis and inflammatory kidney disease

Published today in Cell Reports, researchers from the Integrative Genomics and Medicine (IGM) group at the MRC Clinical Sciences Centre in collaboration with Dr Jacques Behmoaras at Imperial College London and researchers at Yale University discovered new drug targets to treat arthritis and kidney inflammation disease.

By applying a new ‘systems genetics’ approach developed by the IGM group, the study identifies a complex network of 184 genes that express macrophages – cells involved in the innate immune response – which work together to regulate essential cellular processes in inflammatory diseases. One particular gene from the network, Kcnn4, showed the most promise as a potential target in treating arthritis and inflammatory kidney disease.

The protein encoding the Kcnn4 gene is part of a potassium channel that is activated by intracellular calcium and found on the surface of many cells including macrophages. In several inflammatory diseases, macrophages spontaneously clump together into one huge multi-nucleated cell (also called a multinucleated giant cell), a process that is genetically determined and, as MRC researchers have found, occurs spontaneously in rats. This study reveals for the first time that Kcnn4 controls the multinucleation of macrophages and that this is important for an inflammatory kidney disease called glomerulonephritis, a significant cause of renal failure. “By blocking the action of a single gene in the network that control macrophage multinucleation, we ameliorated glomerulonephritis in rats and reduced proteinuria by about 50%, a significant clinical outcome for this disease,” explains Enrico.

In collaboration with Yale University, the researchers also reported a similar therapeutic effect in arthritis mouse models. In bones, osteoclasts are multinucleated macrophages that eat away at bone tissue and reabsorb the nutrients into the body. To retain healthy bones, this process is maintained and bone cells replaced. In arthritis patients however, inflamed joints can prevent the nutrients being replaced, leading to loss of bone density. The study revealed that Kcnn4 could prevent the formation of osteoclasts and subsequent bone erosion and inflammation in mice, alleviating some important symptoms of arthritis.

The discovery of a complex gene network controlling macrophage multinucleation – an essential cellular process occurring naturally under many physiological and pathological conditions – poses a new interesting question. Can the same gene network have a role in other diseases mediated by macrophage multinucleation?

For instance, drugs to block Kcnn4 are already under Phase-III clinical trials for sickle cell anaemia, and long-term treatment with Kcnn4 blockers at therapeutic concentrations showed no discernible toxicity and did not compromise immune responses in rodents. Therefore, the hope is that the same drug can be redirected to treat arthritis and glomerulonephritis in humans. Likewise, other molecules from the large gene network might prove useful as potential therapeutic targets in disease.

“Going beyond the discovery of Kcnn4 as a druggable target for arthritis and inflammatory kidney disease, this study shows how our ‘systems genetics’ strategy has great potential to streamline discovery of genes that can be effectively targeted to treat complex disease. Indeed, in addition to Kcnn4 we discovered another 183 genes, which are involved in macrophage multinucleation and that interact in the cell forming a complex ‘gene network’. This is similar to what can happen in social networks where people interact with each other and can eventually influence important events such as a political election campaign,” says Enrico.

“We believe that other genes in the network could also prove to be promising drug targets to ameliorate inflammatory disease. Testing the effect of this large gene network in disease remains a significant task; yet this study represents an important step forward towards identification of new gene targets, which will impact our ability to move translational research forward,” he adds.

YJ

Reference: Kang H, Kerloc’h A, Rotival M, Xu X, Zhang Q, D’Souza Z, Kim M, Scholz JC, Ko J-H, Srivastava PK, Genzen JR, Cui W, Aitman TJ, Game L, Melvin JE, Hanidu A, Dimock J, Zheng J, Souza D, Behera A, Nabozny G, Cook HT, Bassett JHD, Williams GR, Li J, Vignery A, Petretto E and Behmoaras J. (2014). Kcnn4 is a regulator of macrophage multinucleation in bone homeostasis and inflammatory disease. Cell Reports, 8(4), 1210-24.

This work was supported by the Medical Research Council, Wellcome Trust and Kidney Research UK.

The Medical Research Council has been at the forefront of scientific discovery to improve human health. Founded in 1913 to tackle tuberculosis, the MRC now invests taxpayers’ money in some of the best medical research in the world across every area of health. Twenty-nine MRC-funded researchers have won Nobel prizes in a wide range of disciplines, and MRC scientists have been behind such diverse discoveries as vitamins, the structure of DNA and the link between smoking and cancer, as well as achievements such as pioneering the use of randomised controlled trials, the invention of MRI scanning, and the development of a group of antibodies used in the making of some of the most successful drugs ever developed. Today, MRC-funded scientists tackle some of the greatest health problems facing humanity in the 21st century, from the rising tide of chronic diseases associated with ageing to the threats posed by rapidly mutating micro-organisms. www.mrc.ac.uk