Genetic Discovery Could Lead to Early Detection, Treatment for Osteoarthritis

12 July 2022 12:30

Genetic defects that lead to abnormal inflammation in the hands, hips, knees, and other joints may help explain why some people are more prone to developing severe osteoarthritis than others, according to scientists from the University of Utah Health. Photo credit: Getty Images

An overactive inflammatory response can trigger the most common form of arthritis

A newly detected defect in a genetic signaling pathway that leads to a hyperactive inflammatory response could help explain why some people are more prone to developing severe osteoarthritis than others, according to University of Utah Health scientists. They say the discovery could eventually lead to ways to detect early onset of the disease—even before symptoms appear—and the development of new treatments for the disease.

The findings, among the first to suggest that an increased inflammatory response is a major risk factor in osteoarthritis, appear in the Annals of the Rheumatic Diseases. It is based on a mouse study and analysis of family information derived from the Utah Population Database.

“Researchers have known for a long time that inflammation is part of osteoarthritis, but nothing has conclusively shown that altering the inflammatory process is an early factor in the onset of the disease,” said Michael Jurynec, Ph.D., lead author of the study. and research assistant professor in the Department of Orthopedics and Human Genetics at U of U Health.

“But that’s what our research suggests. Learning as much as we can about this process could allow us to predict who may be susceptible to osteoarthritis and screen for drugs that would block this molecular pathway.”

Osteoarthritis is the most common form of arthritis, affecting more than 32 million Americans, according to the Centers for Disease Control and Prevention (CDC). This disease interferes with the normal function of joints, most commonly in the hands, hips, and knees. As the disease progresses, the cartilage within the joint begins to break down and the underlying bone begins to change. As a result, it causes pain, stiffness, and swelling.

Risk factors include age, obesity, and genetics. For now, there is no cure for osteoarthritis, but exercise, physical therapy, pain medications, and weight loss can help relieve symptoms.

Previously, Jurynec and his colleagues discovered a mutation in a gene that regulates inflammation, called RIPK2, associated with osteoarthritis of the big toe in generations of families in the Utah Population Database.

In this new study, the researchers analyzed the genomes of 150 families in a database that had a pattern of congenital osteoarthritis affecting multiple joints. Altogether, they found six genetic variants affecting proteins in NOD/RIPK2 signal path. Normally, this pathway, which is found throughout the body, helps the immune system fend off bacterial infections. When activated, it temporarily causes inflammation near or around the infection or injury.

Based on these findings, Jurynec and colleagues theorize that genetic mutations in this pathway could amplify or prolong NOD/RIPK2 inflammatory response pathway to joint damage and contributes to the development of osteoarthritis.

Michael Jurynec, Ph.D., lead author of the study and research assistant professor in the Department of Orthopedics and Human Genetics at U of U Health. Photo credit: Charlie Ehlert

“Just finding genes in this family doesn’t necessarily prove that they are the cause of osteoarthritis,” says Jurynec. “That’s why we chose to do animal studies so we can begin to understand how dysregulation of this pathway can increase susceptibility to disease.”

To determine whether mutations in RIPK2 sufficient to induce susceptibility to osteoarthritis, the researchers used the CRISPR/Cas9 gene-editing technology to introduce the defective human amino acid in laboratory mice. They further injure the knee to induce osteoarthritis. Rats are a good model of this process, Jurynec said, because they have essentially the same joint structure as humans.

After eight weeks, the knee joints of mice with humans RIPK2 the mutations showed a significant increase in the degree and severity of cartilage compared to the rodents in the control group. The mice with the human mutation also showed greater activity in the NOD/RIPK2 pathway than the control group, suggesting that it has a major role in the early signs of osteoarthritis that the researchers detected in their knee joints.

Although the study focused on rare mutations found in certain families, Jurynec said the findings could have broad implications for those at risk for the more common forms of osteoarthritis.

“There are likely many ways in which genes in this pathway may be altered by aging, obesity, and other disease conditions,” Jurynec said. “Those changes can predispose a person to osteoarthritis. With that in mind, we might be able to start considering how we identify biomarkers of this pathway that would allow us to identify people who have the disease before the onset of symptoms and find earlier and better treatments.”

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In addition to Jurynec, U of U Health scientists Catherine Gavile, Matthew Honegger, Ying Ma, Shivakumar Veerabhadraiah, Kendra Novak, Kazuyuki Hoshijima, Nikolas Kazmers, and David Grunwald contributed to the study.

The study, “NOD/RIPK2 Signaling Pathways Contributes to Osteoarthritis Susceptibility,” appears in the Annals of the Rheumatic Diseases. It is supported by the Skaggs Foundation for Research, the Utah Genome Project, the Arthritis National Research Foundation, and the National Institute on Aging.

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