Pércio S. Gulko, MD, center, with team members Teresina Laragione, PhD, Assistant Professor of Medicine (Rheumatology), left, and Carolyn Harris, Senior Associate Researcher.
A new gene associated with disease severity in rheumatoid arthritis (RA) has been identified by researchers at the Icahn School of Medicine at Mount Sinai. This finding could provide a new pathway for treatment and a way to measure the prognosis of patients diagnosed with this autoimmune condition.
Through a series of experiments, Pércio S. Gulko, MD, Chief of the Division of Rheumatology, and the Lillian and Henry M. Stratton Professor of Medicine (Rheumatology), and his colleagues showed that Huntingtin-interacting protein 1 (HIP1) is a driver in inflammatory arthritis severity. The findings were published in July 2018 in the Annals of the Rheumatic Diseases. “It is known that this gene is expressed in some cancers, but precisely how it contributed to cancer was not known, and it has never been implicated in inflammation or arthritis. So this new discovery, that it regulates cell invasion, is completely novel,” says Dr. Gulko, senior author of the paper.
Rheumatoid arthritis is a chronic disease affecting more than 1.3 million Americans. The disease causes pain, swelling, and sometimes deformation of joints and affects about 1 percent of the world’s population. In the last 20 years, there have been major advances in the treatment of RA, but the existing treatments immunosuppress patients, increasing the risk for infections.
Dr. Gulko with images of synovial fibroblasts, cells in the joints that are central to his team’s study of rheumatoid arthritis.
“At my laboratory, we have been looking for alternative strategies,” Dr. Gulko says. “We have focused on understanding the regulation of disease severity and joint damage, and this led us to the synovial tissue and the fibroblasts.” These cells are present in all joints and produce the fluid that lubricates and nourishes the cartilage, but in patients with RA, they grow out of control, invading and destroying cartilage and bone.
Dr. Gulko’s team started with rodent models of arthritis, studying animals that were highly susceptible to RA and those that were resistant. Using a technique called positional cloning, the researchers identified gene variants that control arthritis severity and the behavior of the synovial fibroblasts, finding that HIP1 made the cells highly invasive. Next, the team studied synovial fibroblasts from patients with RA and found that HIP1 was strongly expressed in those cells. To test the finding further, the team used a molecular biology technique to “knock down,” or remove, HIP1 from the cells of RA patients, and found that this significantly reduced the cells’ ability to invade.
The team unexpectedly found further evidence implicating HIP1 while collaborating in a study of RA and epigenetics, the environmental influence on genetics. The study, which was published in May 2018 in Nature Communications, compared the synovial fibroblasts of patients with RA with those from patients with osteoarthritis, which is not considered an inflammatory disease. The researchers were looking for dysregulated genes and pathways that differentiated the two groups of patients.
“One key pathway found to be epigenomically dysregulated was the Huntington protein pathway, including HIP1,” Dr. Gulko says.
Going forward, Dr. Gulko has several goals: improving the understanding of how HIP1 regulates disease; finding a way to quantify HIP1 levels in the blood or synovial fluid cells with the aim of creating a predictor of disease prognosis; and developing a drug that would target the HIP1 gene. The ultimate goal is to achieve remission for RA patients.
“I treat many patients with rheumatoid arthritis,” Dr. Gulko says, “and all the work that we have done throughout my career has been centered on trying to bring a benefit to these patients.”