Therapeutic targeting of fibroblast subsets in inflammatory arthritis

Inflammation is a healthy response to tissue damage, which helps to eliminate harmful microbes and repair organs. The factors that cause inflammation and subsequent tissue damage are usually very tightly regulated and opposed by factors that promote resolution and repair. A healthy inflammatory response has a rapid onset and an orderly resolution phase, in which activated immune cells initially recruited from the blood (called leucocytes) , exit the inflamed tissue and the resident tissue cells (called fibroblasts) return to their resting state. However it is not known how the various components of the "ecosystem" in disease are linked together to allow normal function of the affected tissue to be restored with minimal damage. Treatments aimed at leucocytes, traditionally thought to be the villains in arthritis, have proven to be limited in their ability to permanently switch off inflammation and prevent tissue damage. Our work uses new approaches to look directly at what happens to fibroblasts in the joint as arthritis progresses. Fibroblasts are often portrayed as the joint's housekeepers, performing maintenance jobs to keep the joint in good order. However in rheumatoid arthritis, a subset of fibroblasts becomes fundamentally altered. They overgrow, leading to the production of excess fluid and swelling within the joint. Furthermore these fibroblasts turn against the joint and begin to break down cartilage and bone. However there is a problem when it comes to targeting these cells as they come in different varieties, or subsets, only some of which become altered in disease. Our aim is to identify which subsets are most important in the development of arthritis and to explore whether changing them improves disease. Since different fibroblasts perform different functions in the joint, a key objective will be to determine which fibroblasts to target and which to ignore. Very little is known about how fibroblast subsets change during the course of human arthritis. Difficulties in sampling the joints involved and the lack of good fibroblast markers have all proved obstacles to such work. In the last few years we have addressed these limitations head on in the Birmingham Early Arthritis Clinic. Excitingly, in a new collaboration between colleagues in Oxford, Birmingham and Boston (USA) we have found that our new fibroblast markers can discriminate between fibroblasts that will mediate inflammation and cartilage and bone damage. We now plan to use the same markers to explore the fate and function of fibroblasts in an attempt to alter their behaviour. Targeting fibroblasts in this way will lead to a completely new approach to treating inflammatory arthritis; an approach that we are in a unique position to lead. Patients with rheumatoid arthritis in whom clinical remission has been achieved, subsequently relapse once drugs are withdrawn. This suggests that the factors responsible for complete resolution of inflammation remain to be discovered. This is why we are interested in fibroblasts. Our plan is to change the fibroblasts so that the joint can repair. However before we can attempt to do this in humans we have to be sure that we know how many subsets of fibroblasts exist in the joint, what their relationship is to one another and which variety of fibroblasts are responsible for inflammation and which is responsible for tissue damage. Furthermore we need to determine at what point during the course of the disease it is best to change the soil. Altering fibroblasts at the wrong time may make arthritis worse. Altering fibroblasts at the right time might cure the disease