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

Abstract

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.

Molecular Imaging of Folate Receptor β–Positive Macrophages during Acute Lung Inflammation

“…The glycolysis pathway requires folate for one-carbon metabolism (30); therefore, we speculate that activated macrophages express FRb due to increased folate demand for generation of ATP. Although FRb-expressing macrophages have been identified in inflamed human joints and several animal models of inflammatory diseases (11,15,16), our study provides new information regarding functional subsets and phenotype of myeloid cells expressing the receptor and how these cells are recruited to the lungs. In addition, by depleting macrophages, we definitively show that myeloid lineage cells are indeed the target for uptake of folate probe via this receptor.…”

“…Exposure to microbial stimuli and tissue injury has been reported to increase the expression of unique receptors on the surface of activated macrophages, including receptors for folic acid uptake (8)(9)(10)(11)(12). Folic acid is an essential nutrient that functions within the cell to carry one-carbon groups for methylation reactions and for nucleic acid synthesis (13).…”

“…Expression of FRb has also been detected in leukocytes, including a subset of activated macrophages. Macrophage-specific FRb expression has been documented in several inflammatory models and diseases, including rheumatoid arthritis, osteoarthritis, lupus, and cancer (11,15,16). Although FRb has not been studied in the context of acute lung inflammation, expression of this functional, high-affinity FR has proven useful for imaging and targeted therapeutic agent development in other disease settings (10,12,16,17,18).…”

Monitoring Therapy Response of Experimental Arthritis with Radiolabeled Tracers Targeting Fibroblasts, Macrophages, or Integrin αvβ3

“…Put et al provide a review on general tracers and radiolabeled biologicals used to image inflammatory processes (30). Previous studies have focused mostly on targeting macrophages-either with radiolabeled folate (31)(32)(33), with (R)-11 C-PK11195 or translocator protein TSPO (34-36) (which has also been used clinically), or with radiolabeled nanobodies (37)-or by targeting CD163 receptors (38) or mannose receptors (39). Unfortunately, images acquired using radiolabeled folate led to poor-quality images (31), most probably due to general low uptake of the tracers in the joints (32), a feature also seen with the anti-CRIg Nanobody 99m Tc-NbV4m119 (37).…”

Imaging the Folate Receptor on Cancer Cells with 99mTc-Etarfolatide: Properties, Clinical Use, and Future Potential of Folate Receptor Imaging

“…One clinical study showed that 99m Tc-etarfolatide imaging may be more sensitive than physical examination for assessing disease activity in rheumatoid arthritis patients (33). Other FRimaging agents have potential to visualize macrophage activation in osteoarthritis and atherosclerosis (34,35 …”