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Objective. To identify the cells that synthesize EDA-containing fibronectin (FN) and examine the role of EDA+ FN in the pathogenesis of rheumatoid joint lesions.Methods. Localization of EDA+ FN and c-Fos protein in rheumatoid joints was studied immunohistochemically by utilizing antibodies for EDA+ FN and c-Fos. Expression of EDA+ FN was studied by immunoelectron microscopy and in situ hybridization. The amount of EDA+ FN was measured by enzymelinked immunosorbent assay.Results. EDA+ FN was specifically localized in the synovial lining layer of synovium with active rheumatoid arthritis (RA) (n = 17), but not in that with osteoarthritis (n = 4) or with inactive fibrous RA (n = 2).EDA+ FN messenger RNA was localized in the synovial lining layer. EDA+ FN was immunoelectron microscopically localized in the synovial lining fibroblast-like (type B) cells. EDA+ FN was also detected at the cartilagepannus junction and on the surface of RA cartilage. Double staining showed that EDA+ FN colocalized with c-Fos protein in the rheumatoid synovial lining layer. Quantification of EDA+ FN showed that it was highly concentrated in rheumatoid synovial fluids.Conclusion. EDA+ FN is synthesized by the synovial lining fibroblast-like (type B) cells in situ in rheumatoid synovium, and appears to be expressed in association with activated or transformed states of synovium.Fibronectin (FN), synthesized in rheumatoid synovium (1) and specifically located in rheumatoid pannus and on cartilage surface (2,3), may be important in rheumatoid joint destruction (4). FN is composed of more than 2 subunits of protein with molecular weights of 220-250 kd (5). Multiple isoforms of FN are produced from a single gene by alternative splicing at 3 distinct sites: EDA, EDB, and IIICS (5). Recent studies indicate that isoforms containing the EDA or EDB regions are expressed in early stages of fetal development, malignant transformation, and wound healing ( 5 ) , which suggests that EDAcontaining or EDB-containing FN may be expressed in association with cellular proliferation and transformation. The EDA-or EDB-containing FN is found in the synovial lining cells and small blood vessels of rheumatoid joints (6,7), and plasma levels of EDA+ FN in rheumatoid arthritis (RA) patients are higher than those in healthy individuals (8).We used immunohistochemistry techniques to show that EDA+ FN, which is specifically localized in the rheumatoid synovial lining layer, is synthesized by the synovial lining fibroblast-like (type B) cells. EDA+ FN is also detected in invasive fronts of active cellular pannus and on rheumatoid cartilage surfaces that are free of pannus. EDA+ FN is also colocalized with c-Fos protein in the rheumatoid synovial lining layer.Kazuo Hino, BS, Shunichi Shiozawa, MD, Yasuo Kuroki, MD, Hitoshi Ishikawa, MD, Kazuo Chihara, MD: Kobe University, Kobe, Japan; Kazuko Shiozawa, MD: Kakogawa National Hospital, Kakogawa, Japan; Kiyotoshi Sekiguchi, PhD: Osaka Medical Center for Maternal and Child Health, Osaka, Japan; Hisanobu Hirano, MS, Eiji Sakash...

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Synovial fluid EDA(+)Fn can be a predictor of subsequent joint destruction in RA.

Objective. To investigate the role of EDAcontaining fibronectin (EDA+ FN), a splice variant of FN detectable in association with cellular transformation, in the adherence of synovial cells (SC) on rheumatoid cartilage surface.Methods. migration, wound healing, and oncogenic transformation (1). FN is mainly composed of 2 subunits of protein that each have a molecular weight of -250 kd and are connected by disulfide bonds near the carboxyl terminus (2) (Figure 1). Multiple isoforms of FN are produced from a single gene by alternative splicing at 3 distinct sites, EDA, EDB, and IIICS (3). FN produced by hepatocytes and commonly found in plasma, i.e., plasma FN (pFN), lacks the EDA and EDB regions. However, FN produced by most other tissues, i.e., cellular FN, contains the EDA and/or EDB regions of FN in various combinations (4).Previous studies have shown that the level of FN that contains the EDA and/or EDB regions is especially increased during the early stage of fetal development (5), malignant transformation (6), and wound healing (7). Furthermore, studies have indicated that the plasma level of EDA-containing FN (EDA+ FN) is increased in patients with vascular injury (S), malignant tumor (9), and, particularly, rheumatoid arthritis (RA) (10