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

Heijden, J.W. van der; 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

doi:10.1002/art.24219

Cited by 142 publications

(111 citation statements)

References 43 publications

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“…Furthermore, it is clear that multiple signaling molecules produced either by chondrocytes or by neighboring fibroblasts or macrophages can also cause an activity response, as was recently shown by Blom and colleagues (39). Although we investigated the possibility of imaging activated macrophages in experimental OA through FR␤ and demonstrated its presence in experimental OA, this might also create the opportunity to test the effect of specific folate antagonists such as BCG 495 in OA (13).…”

Section: Discussionmentioning

confidence: 93%

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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: 93%

“…It is only after activation that macrophages express the functional form of folate receptor ␤ (FR␤) (11,13). The vitamin folic acid binds to FR␤ with high affinity (K d Ͻ 10 Ϫ9 M).…”

mentioning

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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“…As with all potential disease-modifying strategies in OA, a major obstacle for anti-cytokine therapy in OA will be the difficulty of recruiting patients with early inflammatory OA, before gross bone and cartilage loss is obvious on X-rays and clinical examination. In recent years, some exciting molecular imaging techniques, involving a tracer binding to the macrophage peripheral benzodiazepine receptor, or alternatively folate receptor , have been invented (van der Laken et al, 2008;van der Heijden et al, 2009). Although hitherto published only for RA, there is no reason these methods could not be used also in OA, with the potential to identify a sub-group of patients with a higher degree of macrophage infiltration, or alternatively to correlate success with anti-cytokine approaches with the amount of macrophages detected.…”

Section: The Role Of Synovial Macrophages and Macrophage-produced Medmentioning

confidence: 99%

The Role of Synovial Macrophages and Macrophage-Produced Mediators in Driving Inflammatory and Destructive Responses in Osteoarthritis

Bondeson¹,

Wainwright²,

Hughes³

et al. 2012

Principles of Osteoarthritis- Its Definition, Character, Derivation and Modality-Related Recognition

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“…The glycosylphosphatidylinositol (GPI) membrane anchored FRs can mediate internalization of receptor bound (anti)folate compounds and folate conjugates [25][26][27]. In most normal tissues, FRα is absent, non-functional, or expressed on luminal surfaces doi: 10.7243/2052-6946-2-5 that are inaccessible through the bloodstream [28].…”

Section: Introductionmentioning

confidence: 99%

“…In most normal tissues, FRα is absent, non-functional, or expressed on luminal surfaces doi: 10.7243/2052-6946-2-5 that are inaccessible through the bloodstream [28]. Whereas in pathological tissues including malignant cells and activated macrophages FRα is overexpressed [25][26][27][28][29][30][31][32][33][34][35][36]. This makes FRα as an excellent route for the selective delivery of a broad range of experimental pharmacological agents to these tissues.…”

Section: Introductionmentioning

confidence: 99%

Novel functions of folate receptor alpha in CNS development and diseases

Mayanil¹,

Siddiqui²,

Tomita³

2014

Neurosci Discov

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Abstract(Folate receptor alpha), a GPI-anchored protein is critical for embryonic development. Disruption of both FRα alleles in mice results in pups with a range of malformations and is lethal to the embryos at the time of neural tube closure. Recent body of evidences emphasizes its role in neural tube defects, cerebral folate deficiency, autism and autism spectrum disorders. Circulating autoantibodies against FRα and cerebral folate deficiency appear to play a crucial role in the cause and pathogenesis of a particular subgroup of autism spectrum disorders with co-existing neurological deficits. Since FRα is known to be over-expressed in cancer cells, it has found a novel theranostic role in cancer diagnosis and treatment by using FA-conjugated imaging agents as diagnostic tools and FA-conjugated nanotherapeutics and immunotherapy for cancer. This review highlights some recent advances and novel roles of FRα other than it being just a folate transporter.

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

Cited by 142 publications

References 43 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

The Role of Synovial Macrophages and Macrophage-Produced Mediators in Driving Inflammatory and Destructive Responses in Osteoarthritis

Novel functions of folate receptor alpha in CNS development and diseases

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