Selective expression of folate receptor ? and its possible role in methotrexate transport in synovial macrophages from patients with rheumatoid arthritis

Nakashima-Matsushita, Noriko; Homma, Teiichi; Yu, Shyr-Shen; Matsuda, Takemasa; Sunahara, Nobuhiko; Nakamura, Tadashi; Tsukano, Michishi; Ratnam, Manohar; Matsuyama, Tomohiko

doi:10.1002/1529-0131(199908)42:8<1609::aid-anr7>3.0.co;2-l

Cited by 216 publications

(167 citation statements)

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“…The cell specificity of folate-based imaging has been thoroughly investigated in multiple previous studies, using flow cytometry, confocal microscopy, and in vivo macrophage elimination using clodronate-laden liposomes as determinants for cell phenotyping (11,14,(32)(33)(34). In the present study, an almost total absence of radioactivity in the knee joint after elimination of macrophages using clodronate-laden liposomes was observed.…”

Section: Discussionmentioning

confidence: 99%

Imaging of activated macrophages in experimental osteoarthritis using folate-targeted animal single-photon-emission computed tomography/computed tomography

Piscaer

Müller

Mindt

et al. 2011

Arthritis & Rheumatism

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Objective. Evaluation of macrophage activation may provide essential information about the etiology and progression rate of osteoarthritis (OA). Activated macrophages abundantly express folate receptor ␤ (FR␤), which can be targeted using radioactive-labeled folic acid. This study was undertaken to investigate whether macrophage activation can be monitored in small animal models of OA using a folate radiotracer and to determine whether macrophage activation differs in different models of OA with different OA progression.Methods. Two rat models of OA were used: the mono-iodoacetate (MIA) model, which is a fastprogressing biochemically induced model, and the anterior cruciate ligament transection (ACLT) model, which induces OA at a slower pace. Images were obtained using high-resolution small animal singlephoton-emissioncomputedtomography/computedtomography. The specificity of the technique was tested by eradicating macrophages using clodronate-laden liposomes and blockade of FR␤ by cold folic acid.Results. The MIA model had high initial macrophage activation, with a peak after 2 weeks which disappeared after 8 weeks. The ACLT model showed less activation but was still active 12 weeks after induction. The technique allowed monitoring of the disease process over time, in which late stages of the disease showed less macrophage activation than early stages, especially in the fast-progressing MIA model of OA.Conclusion. Our findings indicate that macrophage activation in experimental OA can clearly be demonstrated and monitored by the folate radiotracer. The high resolution, high sensitivity, and high specificity of the technique allow clear localization of macrophage activity in a disease model that is not known for abundant macrophage involvement.

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Section: Discussionmentioning

confidence: 99%

Imaging of activated macrophages in experimental osteoarthritis using folate-targeted animal single-photon-emission computed tomography/computed tomography

Piscaer

Müller

Mindt

et al. 2011

Arthritis & Rheumatism

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“…hFRβ expression is increased in certain leukemias, most consistently seen in chronic myelogenous leukemia and acute myelogenous leukemia (43,45). hFRβ expression is also increased in activated synovial macrophages, cells involved in the pathogenesis of rheumatoid arthritis and other inflammatory conditions including psoriasis and Crohn's disease (37,39,46,47).…”

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confidence: 99%

Structures of human folate receptors reveal biological trafficking states and diversity in folate and antifolate recognition

Wibowo

Singh

Reeder

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Antifolates, folate analogs that inhibit vitamin B 9 (folic acid)-using cellular enzymes, have been used over several decades for the treatment of cancer and inflammatory diseases. Cellular uptake of the antifolates in clinical use occurs primarily via widely expressed facilitative membrane transporters. More recently, human folate receptors (FRs), high affinity receptors that transport folate via endocytosis, have been proposed as targets for the specific delivery of new classes of antifolates or folate conjugates to tumors or sites of inflammation. The development of specific, FR-targeted antifolates would be accelerated if additional biophysical data, particularly structural models of the receptors, were available. Here we describe six distinct crystallographic models that provide insight into biological trafficking of FRs and distinct binding modes of folate and antifolates to these receptors. From comparison of the structures, we delineate discrete structural conformations representative of key stages in the endocytic trafficking of FRs and propose models for pH-dependent conformational changes. Additionally, we describe the molecular details of human FR in complex with three clinically prevalent antifolates, pemetrexed (also Alimta), aminopterin, and methotrexate. On the whole, our data form the basis for rapid design and implementation of unique, FR-targeted, folate-based drugs for the treatment of cancer and inflammatory diseases.isothermal titration calorimetry | targeted drug delivery

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“…A major distinction between activated and quiescent macrophages lies in their expression of a folate receptor (FR) (11,12). Thus, FR b, a glycosylphosphatidylinositolanchored glycoprotein, is expressed on the surface of activated macrophages (11-13) but essentially absent from the surfaces of resting macrophages and other immune cells.…”

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confidence: 99%

Imaging of Atherosclerosis in Apoliprotein E Knockout Mice: Targeting of a Folate-Conjugated Radiopharmaceutical to Activated Macrophages

Ayala-López¹,

Xia²,

Varghese³

et al. 2010

J Nucl Med

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Early detection of heart disease is essential for the implementation of intervention strategies that reduce the risk of cardiovascular events. Radioimaging methods that have been explored for this purpose include 18 F-FDG, which measures sites of elevated metabolic activity; 99m Tc-annexin A5, which reveals regions of enhanced apoptosis and thrombosis; and 99m Tc-labeled antilectinlike oxidized low-density lipoprotein receptor 1 antibody, which detects the lectinlike oxidized low-density lipoprotein receptor 1 that is overexpressed on a variety of vasculatureassociated cells. In this study, we examine the use of a folatetargeted chelate of 99m Tc, termed 99m Tc-EC20, for imaging of folate receptor (FR)-expressing macrophages that accumulate in atherosclerotic plaques, internalize cholesterol-rich lipoprotein particles, and evolve into foam cells that form components of vulnerable atherosclerotic lesions. Methods: 99m Tc-EC20 was injected into apoliprotein E knockout (apoE2/2) mice fed a normal or Western (high-fat) diet for 25 wk and imaged by g-scintigraphy. Treated mice were also dissected, and radioactivities in excised aortas were quantified by g-counting and imaged by autoradiography. The role of FR-expressing macrophages in uptake of 99m Tc-EC20 was also examined by comparing images of apoE2/2 mice before and after treatment with clodronate liposomes to deplete tissue macrophages, comparing the sites of 99m Tc-EC20 enrichment with sites of macrophage accumulation in thin sections of atherosclerotic tissues, and examining the expression of FRs on atherosclerotic plaquederived macrophages by flow cytometry. Results: ApoE2/2 mice on Western chow exhibited significantly greater accumulation of 99m Tc-EC20 in atherosclerotic lesions than their counterparts on normal chow. The aortas of apoE2/2 mice on a Western diet demonstrated greater numbers of FR-positive macrophages by flow cytometry than did those of apoE2/2 mice on a normal diet. Clodronate liposome treatment significantly reduced the accumulation of 99m Tc-EC20 in atherosclerotic tissues, suggesting that macrophages or monocytes are responsible for uptake of the folate-linked radioimaging agent. Histologic and autoradiographic analysis of tissue sections demonstrated that macrophage accumulation correlated with regions of 99m Tc-EC20 uptake. Conclusion: 99m Tc-EC20 can be used for the imaging of atherosclerosis by selectively targeting FR-positive activated macrophages.

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Selective expression of folate receptor ? and its possible role in methotrexate transport in synovial macrophages from patients with rheumatoid arthritis

Cited by 216 publications

References 40 publications

Imaging of activated macrophages in experimental osteoarthritis using folate-targeted animal single-photon-emission computed tomography/computed tomography

Imaging of activated macrophages in experimental osteoarthritis using folate-targeted animal single-photon-emission computed tomography/computed tomography

Structures of human folate receptors reveal biological trafficking states and diversity in folate and antifolate recognition

Imaging of Atherosclerosis in Apoliprotein E Knockout Mice: Targeting of a Folate-Conjugated Radiopharmaceutical to Activated Macrophages

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