Synovial fibroblasts spread Rheumatoid Arthritis to other joints

New research shows that rheumatoid arthritis synovial fibroblasts help spread destructive arthritis to other joints in the body, according to research by Lefevre and colleagues published online on the 8th November in the journal Nature Immunology.

Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disease that can affect many tissues and organs, but mainly causes inflammation in the lining of the joints. RA is an autoimmune disease and is caused by abnormal immune responses whereby the body’s own immune system attacks itself. About 1% of the population in developed countries suffer from RA, and it leads to progressive joint destruction resulting in chronic pain, loss of mobility and loss of function of the joint. One of the key features of RA is it usually starts in one or two joints and then spreads to most joints in the body. The researchers wanted to understand what host factors are involved in the spread of disease. They were particularly interested in special cells called rheumatoid arthritis synovial fibroblasts (RASFs), which are present in high numbers in rheumatoid synovium (lining of the joint) and had previously been shown to contribute to the progression of RA by attaching to, invading and degrading cartilage and bone.

The researchers used a SCID mouse model of RA. SCID mice have a severe immunodeficiency and cannot mount a humoral or cellular immune response therefore you can graft tissues from another species (in this case human cartilage and RASFs or rheumatoid synovium) subcutaneously (under the skin) and it will not reject it. This means the researchers could study the biology of RA and how it spreads over a long period of time. Using this in vivo model they showed not only that human RASFs attached to, invaded and degraded co-implanted cartilage but also could spread through the mouse body to another cartilage implant on the other side of the mouse (contralateral implant). Experiments that inject RASFs 2 weeks after surgical cartilage implantation suggests that RASF migration was due to neovasculisation (formation of micro blood vessels) of the cartilage and not due to the surgery itself or wound healing. The researchers then implanted rheumatoid synovium as a natural source of RASFs. These “natural” RASFs also migrated to, invaded and degraded the RASF-free cartilage contralateral implant. The organs of 20 mice used in the implant experiments were examined to determine the route of RASF migration; the majority of human RASFs were found in the spleen but no RASFs were detected in the lungs, intestines, heart, liver or skin distant from the implants. Human RASFs were also found in mouse joints and ear cartilage and PCR analysis revealed that human RASFs were present in the bloodstream of experimental mice. Finally, the researchers showed that RASFs are able to transmigrate through cell monolayers, which is an important requirement for entering and leaving the bloodstream at sites of disease or to access distal sites.

This work shows that the characteristic progressive joint destruction seen in RA is in part due to RASFs, which can migrate long distances and spread the destructive arthritis from one primary joint to other joints in the body. More work is needed to understand if other cellular factors are involved in RASF migration. This could provide clues for new drug targets to prevent the spread of RA, which is hugely important since the cause of RA is unknown and there is currently no known cure.

ResearchBlogging.org
Lefèvre, S., Knedla, A., Tennie, C., Kampmann, A., Wunrau, C., Dinser, R., Korb, A., Schnäker, E., Tarner, I., Robbins, P., Evans, C., Stürz, H., Steinmeyer, J., Gay, S., Schölmerich, J., Pap, T., Müller-Ladner, U., & Neumann, E. (2009). Synovial fibroblasts spread rheumatoid arthritis to unaffected joints Nature Medicine DOI: 10.1038/nm.2050

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