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

Joost W. van der Heijden; Ruud Oerlemans; Ben A. C. Dijkmans; Huiling Qi; Conny J. van der Laken; Willem F. Lems; Ann L. Jackman; Maarten C. Kraan; Paul P. Tak; Manohar Ratnam; Gerrit Jansen; MC Kraan

doi:https://doi.org/10.1002/art.24219

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

Joost W. van der Heijden, Ruud Oerlemans, Ben A. C. Dijkmans, Huiling Qi, Conny J. van der Laken, Willem F. Lems, Ann L. Jackman, Maarten C. Kraan, Paul P. Tak, Manohar Ratnam, Gerrit Jansen, MC Kraan

Research output: Contribution to journal › Article › Academic › peer-review

131 Citations (Scopus)

Abstract

OBJECTIVE: To determine the expression of folate receptor beta (FRbeta) 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 FRbeta than methotrexate (MTX). METHODS: Immunohistochemistry and computer-assisted digital imaging analyses were used for the detection of FRbeta protein expression on immunocompetent cells in synovial biopsy samples from RA patients with active disease and in noninflammatory control synovial tissues. FRbeta messenger RNA (mRNA) levels were determined by reverse transcription-polymerase chain reaction analysis. Binding affinities of FRbeta for folate antagonists were assessed by competition experiments for (3)H-folic acid binding on FRbeta-transfected cells. Efficacy of FRbeta-mediated internalization of folate antagonists was evaluated by assessment of antiproliferative effects against FRbeta-transfected cells. RESULTS: Immunohistochemical staining of RA synovial tissue showed high expression of FRbeta 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, FRbeta 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 FRbeta 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 FRbeta-transfected cells. CONCLUSION: Abundant FRbeta 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

Original language	English
Pages (from-to)	12-21
Journal	Arthritis and rheumatism
Volume	60
Issue number	1
DOIs	https://doi.org/10.1002/art.24219
Publication status	Published - 2009

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https://doi.org/10.1002/art.24219

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van der Heijden, J. W., Oerlemans, R., Dijkmans, B. A. C., Qi, H., van der Laken, C. J., Lems, W. F., Jackman, A. L., Kraan, M. C., Tak, P. P., Ratnam, M., Jansen, G., & Kraan, MC. (2009). Folate receptor beta as a potential delivery route for novel folate antagonists to macrophages in the synovial tissue of rheumatoid arthritis patients. Arthritis and rheumatism, 60(1), 12-21. https://doi.org/10.1002/art.24219

@article{b242027b12f9444abbd33ee0acabce2a,

title = "Folate receptor beta as a potential delivery route for novel folate antagonists to macrophages in the synovial tissue of rheumatoid arthritis patients",

abstract = "OBJECTIVE: To determine the expression of folate receptor beta (FRbeta) 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 FRbeta than methotrexate (MTX). METHODS: Immunohistochemistry and computer-assisted digital imaging analyses were used for the detection of FRbeta protein expression on immunocompetent cells in synovial biopsy samples from RA patients with active disease and in noninflammatory control synovial tissues. FRbeta messenger RNA (mRNA) levels were determined by reverse transcription-polymerase chain reaction analysis. Binding affinities of FRbeta for folate antagonists were assessed by competition experiments for (3)H-folic acid binding on FRbeta-transfected cells. Efficacy of FRbeta-mediated internalization of folate antagonists was evaluated by assessment of antiproliferative effects against FRbeta-transfected cells. RESULTS: Immunohistochemical staining of RA synovial tissue showed high expression of FRbeta 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, FRbeta 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 FRbeta 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 FRbeta-transfected cells. CONCLUSION: Abundant FRbeta 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",

author = "{van der Heijden}, {Joost W.} and Ruud Oerlemans and Dijkmans, {Ben A. C.} and Huiling Qi and {van der Laken}, {Conny J.} and Lems, {Willem F.} and Jackman, {Ann L.} and Kraan, {Maarten C.} and Tak, {Paul P.} and Manohar Ratnam and Gerrit Jansen and MC Kraan",

year = "2009",

doi = "https://doi.org/10.1002/art.24219",

language = "English",

volume = "60",

pages = "12--21",

journal = "Arthritis and rheumatism",

issn = "0004-3591",

publisher = "John Wiley & Sons Inc.",

number = "1",

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van der Heijden, JW, Oerlemans, R, Dijkmans, BAC, Qi, H, van der Laken, CJ , Lems, WF, Jackman, AL, Kraan, MC, Tak, PP, Ratnam, M, Jansen, G & Kraan, MC 2009, 'Folate receptor beta as a potential delivery route for novel folate antagonists to macrophages in the synovial tissue of rheumatoid arthritis patients', Arthritis and rheumatism, vol. 60, no. 1, pp. 12-21. https://doi.org/10.1002/art.24219

TY - JOUR

T1 - Folate receptor beta as a potential delivery route for novel folate antagonists to macrophages in the synovial tissue of rheumatoid arthritis patients

AU - van der Heijden, Joost W.

AU - Oerlemans, Ruud

AU - Dijkmans, Ben A. C.

AU - Qi, Huiling

AU - van der Laken, Conny J.

AU - Lems, Willem F.

AU - Jackman, Ann L.

AU - Kraan, Maarten C.

AU - Tak, Paul P.

AU - Ratnam, Manohar

AU - Jansen, Gerrit

AU - Kraan, MC

PY - 2009

Y1 - 2009

N2 - OBJECTIVE: To determine the expression of folate receptor beta (FRbeta) 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 FRbeta than methotrexate (MTX). METHODS: Immunohistochemistry and computer-assisted digital imaging analyses were used for the detection of FRbeta protein expression on immunocompetent cells in synovial biopsy samples from RA patients with active disease and in noninflammatory control synovial tissues. FRbeta messenger RNA (mRNA) levels were determined by reverse transcription-polymerase chain reaction analysis. Binding affinities of FRbeta for folate antagonists were assessed by competition experiments for (3)H-folic acid binding on FRbeta-transfected cells. Efficacy of FRbeta-mediated internalization of folate antagonists was evaluated by assessment of antiproliferative effects against FRbeta-transfected cells. RESULTS: Immunohistochemical staining of RA synovial tissue showed high expression of FRbeta 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, FRbeta 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 FRbeta 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 FRbeta-transfected cells. CONCLUSION: Abundant FRbeta 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

AB - OBJECTIVE: To determine the expression of folate receptor beta (FRbeta) 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 FRbeta than methotrexate (MTX). METHODS: Immunohistochemistry and computer-assisted digital imaging analyses were used for the detection of FRbeta protein expression on immunocompetent cells in synovial biopsy samples from RA patients with active disease and in noninflammatory control synovial tissues. FRbeta messenger RNA (mRNA) levels were determined by reverse transcription-polymerase chain reaction analysis. Binding affinities of FRbeta for folate antagonists were assessed by competition experiments for (3)H-folic acid binding on FRbeta-transfected cells. Efficacy of FRbeta-mediated internalization of folate antagonists was evaluated by assessment of antiproliferative effects against FRbeta-transfected cells. RESULTS: Immunohistochemical staining of RA synovial tissue showed high expression of FRbeta 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, FRbeta 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 FRbeta 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 FRbeta-transfected cells. CONCLUSION: Abundant FRbeta 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

U2 - https://doi.org/10.1002/art.24219

DO - https://doi.org/10.1002/art.24219

M3 - Article

C2 - 19116913

SN - 0004-3591

VL - 60

SP - 12

EP - 21

JO - Arthritis and rheumatism

JF - Arthritis and rheumatism

IS - 1

ER -