Through a series of experiments – on synovial cells from the inner lining of joints in humans and animals, and in animal models of arthritis – researchers from Icahn School of Medicine at Mount Sinai in the US showed that the gene HIP1 is a driver in inflammatory arthritis severity.
This is the first time that HIP1 has been implicated in arthritis severity and in cell invasiveness.
Rheumatoid arthritis is a chronic disease affecting more than 1.3 million Americans. The disease can cause disability and deformation of joints and affects roughly one per cent of the world’s population.
Drugs currently available to treat rheumatoid arthritis target the body’s immune response but raise the risk of immunosuppression and susceptibility to infections such as herpes zoster and pneumonia. “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,” said Percio S Gulko, senior author of the study published in the journal Annals of the Rheumatic Diseases.
“We have focused on understanding the regulation of disease severity and joint damage. Our discovery led us to the synovial fibroblasts, cells inside the joint,” said Gulko.
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, researchers identified a chromosomal region that controls arthritis severity and joint damage. This region contained 41 genes.
Researchers sequenced those genes and discovered a mutation in HIP1, a gene previously unrelated to arthritis or inflammation. They showed that the different forms (alleles) of HIP1 affected the behaviour of the synovial fibroblast, the cells that line the tissue in the inner surface of joints, by reducing or augmenting invasiveness of the cells.
Synovial fibroblast enables local repair and production of the fluid that lubricates joints and nourishes the joint cartilage.
In people with rheumatoid arthritis, the synovial fibroblasts increase in numbers (hyperplasia) and become invasive, and the synovial tissue becomes infiltrated with immune cells, causing joint swelling and pain. This invasive behaviour is known to correlate with joint damage in patients with rheumatoid arthritis.
Researchers experimented with synovial fibroblasts derived from patients with rheumatoid arthritis. They removed the HIP1 gene, which significantly reduced the ability of the rheumatoid arthritis synovial fibroblasts to respond to PDGF (platelet-derived growth factor), a potent inducer of synovial fibroblast invasiveness expressed in increased levels in the joints of patients with rheumatoid arthritis.
Knockdown of HIP1 prevented the activation of the signaling molecule Rac1, which is key for synovial fibroblast invasiveness. Researchers also studied HIP1-deficient mice.
These mice were protected, and developed a milder form of the arthritis.