KCa1.1 Channels in Synovial Fibroblasts
Abstract
This project is relevant to the PRMRP Topic Area Rheumatoid Arthritis. Rheumatoid arthritis (RA) is a disease best known for its effects on joints such as knees and wrists, but it also affects other organs, such as the heart and lungs, and can therefore be deadly. New drugs developed in the last two decades have improved the treatment of RA, but patients with RA still die at an earlier age than the rest of the population. In RA, cells of the immune system mistakenly enter the joints and cause inflammation and damage to the bone and cartilage. Therefore, current medications used to treat RA focus on reducing inflammation and pain. Not all patients with RA see improvement in symptoms with such treatments, and some who do see benefits at first can become resistant and no longer improve with continued treatment. These anti-inflammatory drugs affect many cells in the immune system, weakening it and thus putting the body at much higher risk of cancer and severe infections. As a result, many patients with RA either stop taking their prescribed medications or take them less often, which further reduces their effectiveness in reducing symptoms. We need to make new drugs to treat RA that do not affect cells of the immune system in order to treat those patients who do not gain benefits from existing medications. Immune cells are not the only cells to cause damage to joints during RA. Cells from the joints themselves, called fibroblast-like synoviocytes (FLS) also play a role in the disease. In healthy joints, FLS produce compounds that lubricate the joints to facilitate movement. During RA, however, those cells change their behavior as they start growing on top of each other, crawling around the joints, and also produce compounds that attract immune cells to the joints, that directly destroy bone and cartilage, and that induce the formation of blood vessels in the joints. None of the current therapies for RA selectively target the FLS with a modified behavior (RA-FLS). Finding a way to target RA-FLS, but not immune cells, could lead to the generation of new drugs to treat RA without affecting the immune system. All cells in the body have proteins called ion channels at their surface. These ion channels let ions necessary for cell function, like calcium, zinc, sodium, and many others, in and out of cells. Potassium channels are the ion channels that let potassium ions pass through and different cell types have different potassium channels. Humans have genes for 80 different potassium channel proteins, but these can also be modified and combined so the potassium channels on one cell type are very different from the potassium channels on another cell type. This makes them attractive targets for therapy. We have identified the main potassium channel of human and rat FLS as KCa1.1 and found that whereas it is present in all FLS, its numbers are greatly increased in RA-FLS and in FLS from rats with a disease that mimics RA. If we remove KCa1.1 or use drugs to block its function, we can stop RA-FLS from producing the compounds that attract immune cells and destroy the bone and cartilage. We can also stop RA-FLS from multiplying and from crawling around the joints. If we do the opposite and increase the amount of KCa1.1 on healthy FLS, it induces a change in FLS towards the destructive RA-FLS behavior. When we induce a disease that mimics RA in rats, those treated with KCa1.1 blockers after the start of signs of disease have a reduced disease severity. These findings show that KCa1.1 is an important regulator of RA-FLS and is an attractive target to design drugs that inhibit RA-FLS for the treatment of RA. KCa1.1 is not composed of a single protein. Rather, it contains four proteins called the alpha subunits that assemble to form the KCa1.1 potassium channel. Alpha subunits of KCa1.1 are found in most organs, so targeting them indiscriminately would induce too many side effects. The KCa1.1 alpha gene is very large and contains 22 a
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210598
Entities
People
- Christine Beeton
Organizations
- Baylor College of Medicine
- United States Army