Location, location, location: understanding how the local tissue microenvironment drives inflammation in arthritis

Current treatments for rheumatoid arthritis (RA) do not work well for a large proportion of patients, they do not work at all in some people, nor can they cure or prevent this disease. One major obstacle to developing better drugs is lack of a complete understanding of how inflammatory joint disease arises and progresses. Here, we discuss emerging evidence as to how the tissue microenvironment impacts RA pathogenesis. Each tissue is made up of cells surrounded and supported by a unique extracellular matrix. These complex molecular networks define tissue architecture and provide environmental signals that programme site-specific cell behaviour. In the synovium, a major site of disease activity in RA, both positional and disease stage-specific cellular diversity exists. Improved resolution of the architecture of the synovium, from gross anatomy to the single cell level, in parallel with evidence demonstrating how the synovial extracellular matrix is vital for synovial homeostasis, and how dysregulated signals from the matrix drive chronic inflammation and tissue destruction in the RA joint, have opened up new ways to think about RA pathogenesis, and offer novel therapeutic approaches for people with hard to treat disease, or as a means of disease prevention.