Here, we examine the molecular mechanisms regulating synovial tissue and its destructive behavior in rheumatoid arthritis (RA). The synovial lining is made by the compaction of fibroblast-like synoviocytes (FLS) and macrophages. In inflammatory arthritis, this lining undergoes marked hyperplasia and yields the pannus tissue that extends onto and migrates over the cartilage and degrades it. The major mesenchymal cells of the synovial lining, the FLS, are responsible for producing the destructive enzymes (MMP, MT-MMP and cathepsins) that degrade the cartilage. We found that one of the cadherins, cadherin-11, is expressed in FLS and is a major factor in their cellular adhesion and organization into a synovial lining structure. Further, this synovial cadherin plays a key role in regulating FLS migration, invasion and production of MMPs that are relevant in rheumatoid arthritis. We found that the synovial lining is hyperplastic in cadherin-11 deficts. We will do this by defining the role of cadherin-11 in regulating FLS migration (Part I) and FLS invasion (Part II). In Part I, we will determine how cadherin-11 influences integrin mediated FLS migration on extracellular matrix (ECM) (Aim 1) and how it controls FLS migration over other FLS (Aim 2). We hypothesize that cadherin-11 and its ability to bind p120catenin at its cytoplasmic tail are essential to the process by which FLS respond to potent stimuli to migrate (Aim 3). This includes a process by which FLS """"""""let go"""""""" of existing adhesion contacts by internalizing their adhesion molecules in specialized membrane ruffles, following which actin cytoskeletal reorganization extends the leading edge and pulls up the trailing edge of the cell as it moves forward. New adhesion molecule contacts form to provide attachment and traction for movement. We show how cadherin-11 participates in and regulates these steps in cell migration. Then, in Part II, we show that cadherin-11 blockade oynovium mediates joint damage in rheumatoid arthritis. ? ?

Public Health Relevance

Rheumatoid arthritis affects 1 percent of the population in the U.S. and results in disabling damage to the joints of the body. Inflammation causes pain and swelling and stimulates a special tissue in the joints, called the synovium, to attack and destroy the cartilage. We found a unique molecule that holds the cells of the synovium together. When we block this molecule, it stops how the synovium causes cartilage damage in inflammatory arthritis. We are working out the mechanism by which this occurs in order to understand how to target this molecule in treating rheumatoid arthritis. ? ? ? ????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Arthritis, Connective Tissue and Skin Study Section (ACTS)
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Mancini, Marie
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Brigham and Women's Hospital
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Rao, Deepak A; Gurish, Michael F; Marshall, Jennifer L et al. (2017) Pathologically expanded peripheral T helper cell subset drives B cells in rheumatoid arthritis. Nature 542:110-114
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