Osteoarthritis is a painful condition in which cartilage - the protective cushioning between the joints - gradually breaks down. The progressive joint disease, which affects over 32 million people in the United States, can eventually cause bone-on-bone friction, joint stiffness, and pain with every movement.
Multiple factors can influence a person's risk of developing osteoarthritis, including injury, obesity, aging, and genetics. Recent research has found that nearly half of the risk for osteoarthritis is genetic, which has raised interest in using genetic data to develop a therapy that can stop joint tissue from degrading further.
But for a new therapy to be developed, researchers must first identify the genes that directly contribute to the development of osteoarthritis, termed "causal" genes. A multidisciplinary team of researchers at the UNC Thurston Arthritis Research Center, comprised of Doug Phanstiel, PhD, Richard F. Loeser, Jr., MD, and Brian Diekman, PhD, at the UNC School of Medicine have done just that.
A new study by the group has identified 13 genes, termed "high probability risk genes," that directly contribute to joint tissue loss and greatly increase a person's chances of developing osteoarthritis. Their results, which were published in Cell Genomics, has filled a considerable knowledge gap in the effort to define genetic targets for therapies.
Richard F. Loeser, Jr., MD
"There have been a number of studies that have identified over 100 'risk regions' within DNA for osteoarthritis, but few have found causal genes," said Loeser, who is director of the UNC TARC and the Joseph P. Archie, Jr. Eminent Professor of Medicine at the UNC School of Medicine. "If we can identify the causal genes, we can use that information to define new genetic targets for therapies for osteoarthritis."
Osteoarthritis is the most common form of arthritis. Rheumatologists, like Loeser, often recommend nonsteroidal anti-inflammatory drugs, exercise, and weight loss to help patients with osteoarthritis to manage their symptoms. As of right now, nothing can stop the disease from progressing.
The latest study began back in 2022, when Phanstiel, Loeser, and Diekman received a $2.5 million grant from the National Institute of Arthritis and Musculoskeletal and Skin Diseases to identify new osteoarthritis risk genes that could be further studied for therapeutic development.
The team brought together multiple areas of expertise to perform their collaborative research initiative. Loeser's lab first collected joint tissue from over 100 human donors to build a cellular model of the disease. After growing the cells in the lab and introducing them to molecules that induced an osteoarthritis-like state, they could study the condition in a living, controlled environment.
Brian Diekman, PhD
Phanstiel, who is an associate professor in the Department of Cell Biology and Physiology, then leveraged his lab's expertise in genomics and bioinformatics to generate the gene expression data and computationally identify the genes associated with osteoarthritis risk. Brian Diekman, PhD, an associate professor at the UNC-NC State Joint Department of Biomedical Engineering and an expert on gene editing, led follow up studies to determine what role the causal genes were playing in osteoarthritis.
Using a genomics approach, they identified 13 genes that have a high probability of influencing genetic risk of osteoarthritis. Six of the thirteen genes are brand new to scientists, in terms of their connections to the joint disease. The newly discovered genes are notable in that they can provide new insights into an array of biological processes that may be contributing to the osteoarthritis.
"Some of these genes have known roles in osteoarthritis or are involved in processes relevant to osteoarthritis pathology, while the function of others is less clear," said Phanstiel, who is also a member of UNC Lineberger Comprehensive Cancer Center. "It is possible, even likely, that osteoarthritis risk is driven by genetic influences on a number of different processes that act across a diverse array of developmental time points and biological conditions."
With these 13 genes now identified, the research team plans to continue their work on multiple fronts. First and foremost, the team is expanding their current study to include samples from a larger cohort of donors and multiple cell types, in order to identify more genes that are associated with osteoarthritis.
Researchers are also performing studies to better understand the biological processes that are being initiated by their newly identified causal genes. At the same time, the team is currently conducting drug screening studies to find drug compounds that target the biological pathways of interest.
"The hope is that we will be able to find new therapeutics that will stop the progression of joint damage at its earliest stages, preventing the development of pain and disability experienced by the many patients suffering with osteoarthritis," said Loeser.
