Folate receptor β as a potential delivery route for novel folate antagonists to macrophages in the synovial tissue of rheumatoid arthritis patients

Objective To determine the expression of folate receptor β (FRβ) in synovial biopsy tissues and peripheral blood lymphocytes from rheumatoid arthritis (RA) patients and to identify novel folate antagonists that are more selective in the targeting and internalization of FRβ than methotrexate (MTX). M...

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Published in:Arthritis and rheumatism 2009-01, Vol.60 (1), p.12-21
Main Authors: Van Der Heijden, Joost W., Oerlemans, Ruud, Dijkmans, Ben A. C., Qi, Huiling, Laken, Conny J. Van Der, Lems, Willem F., Jackman, Ann L., Kraan, Maarten C., Tak, Paul P., Ratnam, Manohar, Jansen, Gerrit
Format: Article
Language:English
Subjects:
Animals
Arthritis, Rheumatoid - drug therapy
Arthritis, Rheumatoid - immunology
Arthritis, Rheumatoid - pathology
Biological and medical sciences
Biopsy
Carrier Proteins - genetics
Carrier Proteins - metabolism
Cell Division - drug effects
CHO Cells
Cricetinae
Cricetulus
Diseases of the osteoarticular system
Folate Receptors, GPI-Anchored
Folic Acid Antagonists - pharmacokinetics
Humans
Immunohistochemistry
Inflammatory joint diseases
Macrophages - immunology
Macrophages - metabolism
Macrophages - pathology
Medical sciences
Receptors, Cell Surface - genetics
Receptors, Cell Surface - metabolism
RNA, Messenger - metabolism
Synovial Membrane - immunology
Synovial Membrane - pathology
Transfection
Tritium
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Summary:Objective To determine the expression of folate receptor β (FRβ) in synovial biopsy tissues and peripheral blood lymphocytes from rheumatoid arthritis (RA) patients and to identify novel folate antagonists that are more selective in the targeting and internalization of FRβ than methotrexate (MTX). Methods Immunohistochemistry and computer‐assisted digital imaging analyses were used for the detection of FRβ protein expression on immunocompetent cells in synovial biopsy samples from RA patients with active disease and in noninflammatory control synovial tissues. FRβ messenger RNA (mRNA) levels were determined by reverse transcription–polymerase chain reaction analysis. Binding affinities of FRβ for folate antagonists were assessed by competition experiments for 3H‐folic acid binding on FRβ‐transfected cells. Efficacy of FRβ‐mediated internalization of folate antagonists was evaluated by assessment of antiproliferative effects against FRβ‐transfected cells. Results Immunohistochemical staining of RA synovial tissue showed high expression of FRβ on macrophages in the intimal lining layer and synovial sublining, whereas no staining was observed in T cell areas or in control synovial tissue. Consistently, FRβ mRNA levels were highest in synovial tissue extracts and RA monocyte‐derived macrophages, but low in peripheral blood T cells and monocytes. Screening of 10 new‐generation folate antagonists revealed 4 compounds for which FRβ had a high binding affinity (20–77‐fold higher than for MTX). One of these, the thymidylate synthase inhibitor BCG 945, displayed selective targeting against FRβ‐transfected cells. Conclusion Abundant FRβ expression on activated macrophages in synovial tissue from RA patients deserves further exploration for selective therapeutic interventions with high‐affinity–binding folate antagonists, of which BCG 945 may be a prototypical representative.
ISSN:0004-3591
1529-0131
DOI:10.1002/art.24219