title: In vivo imaging of cell proliferation enables the detection of the extent of experimental rheumatoid arthritis by 3'-deoxy-3'-18f-fluorothymidine and small-animal PET.
abstract: The aim of this work was to study the feasibility of measuring cell proliferation noninvasively in vivo during different stages of experimental arthritis using the PET proliferation tracer 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT).
  
  
  METHODS
  We injected mice with serum containing glucose-6-phosphate-isomerase-specific antibodies to induce experimental arthritis, and we injected control mice with control serum. Animals injected with (18)F-FLT 1, 3, 6, and 8 d after the onset of disease were analyzed in vivo by PET, PET/CT, or PET/MR imaging followed by autoradiography analysis. The (18)F-FLT uptake in the ankles and forepaws was quantified on the basis of the PET images by drawing standardized regions of interest. To correlate the in vivo PET data with cell proliferation, we performed Ki-67 immunohistochemistry of diseased and healthy joints at the corresponding time points.
  
  
  RESULTS
  Analysis of the different stages of arthritic joint disease revealed enhanced (18)F-FLT uptake in arthritic ankles (2.2 ± 0.2 percentage injected dose per gram [%ID/g]) and forepaws (2.1 ± 0.3 %ID/g), compared with healthy ankles (1.4 ± 0.3 %ID/g) and forepaws (1.5 ± 0.5 %ID/g), as early as 1 d after the glucose-6-phosphate-isomerase serum injection, a time point characterized by clear histologic signs of arthritis but only slight ankle swelling. The (18)F-FLT uptake in the ankles (3.5 ± 0.3 %ID/g) reached the maximum observed level at day 8. Ki-67 immunohistochemical staining of the arthritic ankles and forepaws revealed a strong correlation with the in vivo (18)F-FLT PET data. PET/CT and PET/MR imaging measurements enabled us to identify whether the (18)F-FLT uptake was located in the bone or the soft tissue.
  
  
  CONCLUSIONS
  Noninvasive in vivo measurement of cell proliferation in experimental arthritis using (18)F-FLT PET is a promising tool to investigate the extent of arthritic joint inflammation.
authors.affiliation: Laboratory for Preclinical Imaging and Imaging Technology of the Werner Siemens-Foundation, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University, Tübingen, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Fuchs
authors.forename: Ursula
authors.initials: U
authors.lastname: Kohlhofer
authors.forename: Leticia
authors.initials: L
authors.lastname: Quintanilla-Martinez
authors.forename: Denis
authors.initials: D
authors.lastname: Lamparter
authors.forename: Ina
authors.initials: I
authors.lastname: Kötter
authors.forename: Gerald
authors.initials: G
authors.lastname: Reischl
authors.forename: Martin
authors.initials: M
authors.lastname: Röcken
authors.forename: Bernd J
authors.initials: BJ
authors.lastname: Pichler
authors.forename: Manfred
authors.initials: M
authors.lastname: Kneilling
mesh_terms: D000818:Animals; D001172:Arthritis, Rheumatoid / Q000139:chemically induced / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology*; D001692:Biological Transport; D049109:Cell Proliferation; D015224:Dideoxynucleosides / Q000378:metabolism; D005240:Feasibility Studies; D005260:Female; D005786:Gene Expression Regulation; D005956:Glucose-6-Phosphate Isomerase / Q000009:adverse effects; D019394:Ki-67 Antigen / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D051379:Mice; D008807:Mice, Inbred BALB C; D064847:Multimodal Imaging; D049268:Positron-Emission Tomography; D014057:Tomography, X-Ray Computed
chemical_list: D015224:Dideoxynucleosides; D019394:Ki-67 Antigen; D005956:Glucose-6-Phosphate Isomerase; C002854:alovudine