Could a cure for OA be as simple as flicking a switch?

Could a cure for OA be as simple as flicking a switch?

Epigenetics to put it simply is the study of biological mechanisms that turn our genes on and off. It addresses how environmental inputs impact gene activity. Altering gene activity controls when and how much protein a gene makes, which in turn controls a multitude of biological processes. Epigenetics is everywhere your diet, where you live, who you interact with, when you sleep, how you exercise, even aging – all of these can ultimately cause chemical modifications around the genes that will turn those genes on or off over time.

Winds of change in Autoimmune Treatment

Autoimmune conditions are complex with multitude of causes. This presents a challenge to researchers both in trying to understand the origins and progression of these conditions as well as in the development of successful treatments. Over the last ten years numerous publications have shown an association between epigenetics and autoimmune conditions. Despite the enormous strides that have been made in this field of research much work remains in order to determine if this association is also causative, answering the question of whether these epigenetic changes lead to development of autoimmune conditions. Improved understanding of epigenetic regulation as well as novel modular technologies allowing precise targeting of specific proteins within the nucleus, at specific DNA locations, has led rapid development of the field of epigenetic engineering. Editing of epigenetic factors is pegged as a potential game changer for our understanding and treatment of autoimmune conditions.

A Circle of Influence

Dr Matlock Jefferies is a physician and researcher that is delving into the world of epigenetics in order to find new osteoarthritis (OA) treatments. Both of Dr Jefferies’ parents have early, rapidly progressive knee OA. During his research training he realized just how common a disease OA is. It also become apparent that there are no effective treatments other than joint replacement. His interest in how epigenetics contribute to OA was sparked in the very first laboratory he worked in. As a newly created laboratory Dr Jefferies worked very closely in a one on one capacity with the head of the laboratory, Dr Sawalha. The time he spent in this capacity cemented his desire to work on better OA treatment options approaching it through improved understanding of the role of epigenetics. As a physician and researcher, he sees the real-life impact and importance of undertaken research in this field.

Earlier work led to discovering that there are differences in DNA methylation patterns in joint tissue from human OA patients compared to samples from healthy individuals. DNA methylation is a process in which methyl groups are added to DNA molecules. This can change the activity of the DNA sequence without altering the sequence itself. When this occurs in a gene promoter, it typically results in repression of that gene’s activity. In mammals, DNA methylation of genes is associated with a number of key processes, including aging, which is frequently the biggest risk factor associated with OA. Epigenetic modifications such as this could therefore be a tool to track progression of diseases such as OA as well as othering potential new therapeutic targets by turning certain genes in certain locations on or off.

Putting Epigenetics on the Map

Funds from the ANRF grant were employed to create a large-scale epigenetics study. “ANRF allowed me to pursue an innovative project without a substantial amount of preliminary data, and gave me enough money to actually make it happen. It is also quite an honor to be awarded an ANRF grant as ANRF grants carry a lot of weight in the rheumatology and arthritis community.” Using a mouse model Dr Jefferies is hoping to tease out which epigenetic differences are related to the most common risk factors for OA. Simply put it looks at the environmental factors that change a gene’s activity thus resulting in abnormal consequences that lead to autoimmune conditions. In order to do this the team introduces OA risk factors individually and then examine epigenetic changes within knee cartilage. For example, OA is induced in mice, the impact of factors such as age and diet induced obesity are then added and assessed paying attention to resulting epigenetic differences. Cumulatively this data will be used to produce the first-of-its-kind detailed epigenetic map of mouse knee cartilage while defining the changes that occur as OA develops. Using whole-genome bisulfite sequencing a complete picture of the epigenetic changes occurring throughout the mouse genome will hopefully be revealed.

“I am hoping that we will be able to define the specific epigenetic changes that are associated with reversible risk factors (obesity) compared to those which are not reversible (due to aging or trauma). This will offer us considerable insight into potential future therapies, which could focus efforts on blocking or activating those genes and pathways which the patient will be unable to. Furthermore, by performing the first large-scale whole-genome epigenetic study, I hope that we will find additional drug targets which undergo epigenetic changes that have been missed by previous studies using microarrays that only cover parts of the genome.”

 


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ANRF
Article Author
Arthritis National Research Foundation
arthritisresearch@curearthritis.org

The Arthritis National Research Foundation's mission is to provide initial research funding to brilliant, investigative scientists with new ideas to cure arthritis and related autoimmune diseases. Writing articles about the patients affected and the science being done to find a cure shows why we need to come together to #CureArthritis!

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