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A potential pathway for treatment and a way to assess the prognosis of patients with rheumatoid arthritis.
A gene associated with disease severity in models of rheumatoid arthritis (RA) has been identified by researchers at the Icahn School of Medicine at Mount Sinai in New York. The discovery could provide a new pathway for treatment and a way to assess the prognosis of patients with RA.
Percio S. Gulko, MD, Chief of the Division of Rheumatology, Lillian and Henry M. Stratton Professor of Medicine (Rheumatology), and senior author on the paper, and his colleagues demonstrated that the Huntingtin-interacting protein 1 (HIP1) gene is a driver in the severity of inflammatory arthritis. This is the first time that HIP1 has been implicated in arthritis severity and in cell invasiveness.
The results of their study appear online in the Annals of the Rheumatic Diseases.
“There have been major advances in the treatment of rheumatoid arthritis in the past 20 years, but disease remission still remains uncommon. Most drugs today target inflammation but often that is not enough to control disease,” says Dr. Gulko. “At my laboratory, we have been looking for alternative strategies. In this research, we have focused on understanding the regulation of disease severity and joint damage. Our discovery led us to the synovial fibroblasts.”
Through genetic strategies including linkage mapping and congenic breeding, in which specific chromosome fragments in arthritis-susceptible rodent strains are replaced with chromosome fragments from arthritis-resistant strains, Dr. Gulko and his co-researchers identified a chromosomal region that controls arthritis severity and joint damage.
This region contains 41 genes. The investigators sequenced those genes and discovered a mutation in HIP1, a gene previously unrelated to arthritis or inflammation. They were then able to show that the different alleles of HIP1 affected the behavior of synovial fibroblasts by reducing or augmenting invasiveness of the cells. This invasive behavior is known to correlate with joint damage in patients with RA.
Next, the researchers knocked down the HIP1 gene in synovial fibroblasts derived from patients with RA. Removal of the HIP1 gene significantly reduced the ability of the synovial fibroblasts to respond to PDGF (platelet-derived growth factor), a potent inducer of synovial fibroblast invasiveness. Knockdown of HIP1 prevented the activation of the signaling molecule Rac1, which is key for synovial fibroblast invasiveness.
Dr. Gulko and his colleagues also studied HIP1-deficient mice. These mice were protected and developed a milder form of the arthritis.
Next: Implications for future therapy
“These new discoveries raise the future possibility of targeting HIP1 to treat rheumatoid arthritis, and also of quantifying HIP1 levels in the blood or synovial fluid cells to predict disease outcome,” said Dr. Gulko.
Dr. Gulko’s research provides a framework for a potential new target for therapy and, perhaps, a new predictor of a patient’s prognosis. He and his colleagues plan to investigate the feasibility of a drug that would target the HIP1 gene. “We are aiming for a novel way of treating the disease. One that targets the synovial fibroblast, while sparing the immune system outside the joint,” he says.
Laragione T, Brenner M, Lahiri A, et al. Huntingtin-interacting protein 1 (HIP1) regulates arthritis severity and synovial fibroblast invasiveness by altering PDGFR and Rac1 signalling. Ann Rheum Dis. 26 July 2018. doi: 10.1136/annrheumdis-2018-213498.
Researchers identify new arthritis severity gene [press release]. New York, NY: Icahn School of Medicine at Mount Sinai; July 26, 2018.