Microarrays demystified.

Fibroblast activation protein (FAP), as described so far, is a type II cell surface serine protease expressed by fibroblastic cells in areas of active tissue remodelling such as tumour stroma or healing wounds. We investigated the expression of FAP by fibroblast-like synoviocytes (FLSs) and compared the synovial expression pattern in rheumatoid arthritis (RA) and osteoarthritis (OA) patients. Synovial tissue from diseased joints of 20 patients, 10 patients with refractory RA and 10 patients with end-stage OA, was collected during routine surgery. As a result, FLSs from intensively inflamed synovial tissues of refractory RA expressed FAP at high density. Moreover, FAP expression was co-localised with matrix metalloproteinases (MMP-1 and MMP13) and CD44 splice variants v3 and v7/8 known to play a major role in the concert of extracellular matrix degradation. The pattern of signals appeared to constitute a characteristic feature of FLSs involved in rheumatoid arthritic joint-destructive processes. These FAP-expressing FLSs with a phenotype of smooth muscle actin-positive myofibroblasts were located in the lining layer of the synovium and differ distinctly from Thy-1expressing and non-proliferating fibroblasts of the articular matrix. The intensity of FAP-specific staining in synovial tissue from patients with RA was found to be different when compared with end-stage OA. Because expression of FAP by RA FLSs has not been described before, the findings of this study highlight a novel element in cartilage and bone destruction of arthritic joints. Moreover, the specific expression pattern qualifies FAP as a therapeutic target for inhibiting the destructive potential of fibroblast-like synovial cells. Introduction Fibroblast activation protein (FAP) is an Mr 95-kDa, cell surface-bound, type II transmembrane glycoprotein and belongs to the family of serine prolyl oligopeptidases. Comparison of amino acid sequences indicates that FAP is essentially identical to seprase [1] and closely related to dipeptidylpeptidase IV (DPP IV), also known as CD26, another type II integral membrane protein [2]. These exoproteases cleave NH2-terminal dipeptides from polypeptides with l-proline or l-alanine in the penultimate position. In addition, FAP was found to bear collagenase activity in vitro [1,3]. Peptidase activity of FAP, in addition to various families of proteolytic enzymes such as matrix or disintegrin metalloproteases that serve as major collagenases, contributes to extracellular matrix (ECM) degradation [4,5]. This not only is a fundamental property of normal tissue repair and remodelling but also is involved in the pathological processes of invasive growth. It correlates with the expression of FAP in granulation tissue of healing wounds and in more than 90% of human epithelial carcinomas [6]. Consistent with its mesenchymal origin, FAP is also occasionally expressed by