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Noninvasive Imaging of Osteoclasts in Parathyroid Hormone–Induced Osteolysis Using a ⁶⁴Cu-Labeled RGD Peptide

¹ Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri; ² Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri; and ³ Department of Medicine, Washington University School of Medicine, St. Louis, Missouri

View larger version (10K): [in this window] [in a new window]   FIGURE 1.  Structure of CB-TE2A-c(RGDyK).

View larger version (48K): [in this window] [in a new window]   FIGURE 2.  Uptake of 64Cu-CB-TE2A-c(RGDyK) by osteoclasts and macrophages. BMMs were harvested from mice and grown in culture. (A) Cells treated with only M-CSF remained TRAP(–) mononuclear macrophages. (C) Cells cultured in presence of MCSF plus RANKL differentiated into large, TRAP(+) osteoclasts (red stain). (B) Cell uptake was determined 2 h after addition of 64Cu-CB-TE2A-c(RGDyK) (4 nM) plus c(RGDyK) (0–4,000 nM) to medium of cells grown in 6-well plates. Each data point represents average of triplicate measurements. (D) Integrin expression was evaluated by Western blot against ß3. Lanes: 1 = vß3 standard, 10 ng; 2 = empty; 3 = osteoclast lysate, 20 µg; 4 = macrophage lysate, 20 µg.

View larger version (17K): [in this window] [in a new window]   FIGURE 3.  PTH induces osteoclasts resulting in increased uptake of 64Cu-CB-TE2A-c(RGDyK) at calvarium. TRAP-stained sections of calvarium of control mice (A) and PTH-treated mice (D) confirm osteoclast induction after PTH treatment. Osteoclasts stain red. (B) Biodistribution (1 h after injection) was performed on control mice (n = 8), PTH-treated mice (n = 8), and PTH-plus-block mice injected with 740 kBq (20 µCi) (10.5–12 ng) of 64Cu-CB-TE2A-c(RGDyK). Note that n = 7 for PTH femur because of contamination of 1 sample by urine. (C) Uptake of 64Cu-CB-TE2A-c(RGDyK) (biodistribution 1 h after injection: control, n = 7; PTH, n = 7) was plotted against ratio of osteoclast surface area to total surface area.

View larger version (21K): [in this window] [in a new window]   FIGURE 4.  Small-animal PET/CT of PTH-treated mice. Calvarium uptake of 64Cu-CB-TE2A-c(RGDyK) was higher in PTH-treated mice (7.4 MBq [199 µCi],115 ng, SUV = 0.53) than in control mice (7.7 MBq [209 µCi], 121 ng, SUV = 0.22) (50- to 60-min summed dynamic image) (A). In PTH-treated mice, uptake was reduced in all tissues, including calvarium, after injection of c(RGDyK) (PTH [left]: 159 µCi, 84 ng, SUV = 0.33; block [right]: 164 µCi, 87 ng, SUV = 0.18) (static image obtained 60 min after injection, 10-min scan) (B). Arrowheads indicate calvarium of each animal. Fiducials (*) are indicated.