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Abstract

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 MMP-13) 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-1-expressing 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.

Treatment of malignant pleural mesothelioma by fibroblast activation protein-specific re-directed T cells

“…To estimate the effect of re-directed FAP-specific T cells in chronically inflamed tissue, we used activated fibroblasts from patients with rheumatoid arthritis out of the effusion from inflamed joints. As reported, the herein used activated fibroblasts isolated from different donors expressed FAP [37]. Therefore, the strong and antigen-specific lysis of fibroblasts derived from inflamed tissue by re-directed FAP-specific T cells was expected.…”

A Single-Agent Dual-Specificity Targeting of FOLR1 and DR5 as an Effective Strategy for Ovarian Cancer

“…Since FAP is also over-expressed in the disease-associated stroma of wound healing tissues and multipotent bone marrow stem cells, FAP targeting does not give specificity to the tumor. Therefore, toxicities due to non-selective activity are inevitable (Bauer et al, 2006; Tran et al, 2013). Likewise, co-administration of Apo2L and AMG-655 has been reported to enhance DR5 activity (Graves et al, 2014).…”

Fibroblast activation protein

“…15 FAP is also expressed during diseases associated with activated stroma, including wound healing, rheumatoid arthritis, osteoarthritis, cirrhosis and pulmonary fibrosis. [16][17][18][19][20] Thus, the function of FAP in tissue remodeling becomes an intriguing topic. FAP is expressed selectively by cancer-associated fibroblasts (CAFs) and pericytes rather than tumor cells in more than 90% of human epithelial malignancies, including colorectal, ovarian, breast, bladder and lung.…”