Cadherins are integral membrane adhesion proteins that mediate homophilic adhesion (bind to cadherins of the same type) on cells within a tissue. During development they mediate the sorting of cells into tissues and in adults the integrity and architecture of tissues. Cadherin expression and signaling are also known to participate in regulating cell proliferation, migration and invasion. For example, loss of E-cadherin (E-cad) expression that mediates integrity of the epithelium, is associated with epithelial cell progression to malignancy, invasion and metastases. Normal synovium is a tissue of a few cells thick composed of Type A, monocyte-like synoviocytes (MLS) and Type B, fibroblast-like synoviocytes (FLS). Yet the synovial lining is neither a true epithelium nor endothelium as it lacks a basement membrane. We hypothesize that a distinct cadherin might be expressed on synoviocytes and play a role in making the synovium a tissue. We identified cadherin-11 (cad-11) expressed by the type B FLS, but not by fibroblasts in skin, gut, or various other tissues. Here we show preliminary data that cad-11 influences the proliferation, adhesion and cytoskeletal organization of FLS. Thus, we propose to define the role of cad-11 in influencing the proliferation of FLS cultured in the presence of cad-11 expressing cells or plate-bound cad-11 fusion proteins coated on plastic wells. Effects on the major signaling pathways affecting FLS activation, proliferation, apoptosis, migration and invasion will be determined, since these features bear relevance to the abnormal proliferation and invasion characteristics of synovial cells in the rheumatoid pannus. We have previously described that lymphocytes bind E-cadherin via the alphaEbeta7 leukocyte integrin (a heterophilic interaction). Here, we propose to identify the lymphocyte receptor that mediates adhesion to cad-11, as it may play an important role in lymphocyte adhesion and localization in the inflamed synovium. Finally, we have confirmed expression of cad-11 in a mouse model of synovitis and will administer anti-cad-11 mAb and cad-11-Fc to assess the potential value of cad-11 as a therapeutic target in inflammatory synovitis. Together, these studies are likely to yield new insights into the biology of synoviocytes and identify a new biotherapeutic target (the synovial cadherin) having potential relevance to rheumatoid arthritis.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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General Medicine A Subcommittee 2 (GMA)
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Gretz, Elizabeth
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Brigham and Women's Hospital
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