EXTENDED REPORT

Anchorage on fibronectin via VLA-5 (5ß1 integrin) protects rheumatoid synovial cells from Fas-induced apoptosis

A Kitagawa¹, Y Miura^1,2, R Saura^1,2, M Mitani¹, H Ishikawa^1,2, A Hashiramoto¹, S Yoshiya¹, S Shiozawa², M Kurosaka¹

¹ Department of Orthopaedic Surgery, Kobe University School of Medicine, Japan
² Department of Rheumatology, Faculty of Health Sciences, Kobe University School of Medicine, Japan

Correspondence to:
Dr Y Miura
Department of Rheumatology, Faculty of Health Sciences, Kobe University School of Medicine, Japan; miura{at}kobe-u.ac.jp

Background: Rheumatoid synovial cells are resistant to apoptosis induction in vivo, whereas, fibroblast-like synovial cells in rheumatoid arthritis (RA-FLS) are vulnerable to Fas-induced apoptosis in vitro.

Objective: To clarify this discrepancy by studying the contribution of the interaction between cellular integrin and matrix fibronectin (Fn), which is significantly increased in the rheumatoid joints, to the induction of apoptosis in RA-FLS.

Methods: Integrin and Fas mRNAs were measured by reverse transcription-polymerase chain reaction in RA-FLS. Integrins expressed in rheumatoid synovial tissues were analysed by immunohistochemistry. RA-FLS plated either on Fn or on control poly-L-lysine were incubated with agonistic anti-Fas monoclonal antibodies (mAbs). Apoptosis induction was evaluated using terminal deoxynucleotidyl transferase mediated UTP nick end labelling (TUNEL) and immunoblotting for caspase-3 and poly (ADP-ribose) polymerase in the presence or absence of anti-VLA-5 mAb.

Results: VLA-5 (5ß1 integrin), a major integrin expressed on RA-FLS, was required for the adhesion of RA-FLS on Fn. RA-FLS plated on Fn were more resistant to Fas-induced apoptosis than those plated on control poly-L-lysine. This protection by Fn was reversed by anti-VLA-5 mAb.

Conclusion: Anchorage of RA-FLS on matrix Fn via VLA-5 protects RA-FLS from Fas-induced apoptosis, and Fn abundantly present in rheumatoid synovium appears to afford RA-FLS resistance against apoptosis induction in vivo.

Abbreviations: DMEM, Dulbecco’s modified Eagle’s medium; ECM, extracellular matrix; Fn, fibronectin; mAb, monoclonal antibody; PARP, poly (ADP-ribose) polymerase; PBS, phosphate buffered saline; pLL, poly-L-lysine; RA, rheumatoid arthritis; RA-FLS, fibroblast-like synovial cells in rheumatoid arthritis; RT-PCR, reverse transcription-polymerase chain reaction; TdT, terminal deoxynucleotidyl transferase; TUNEL, terminal deoxynucleotidyl transferase mediated UTP nick end labelling

Keywords: integrin; apoptosis; Fas; rheumatoid synovial cell; rheumatoid arthritis; fibronectin

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