Abstract
Purpose
The goal of this study was to determine the specificity of 64Cu-CB-TE2A-c(RGDyK) (64Cu-RGD) for osteoclast-related diseases, such as Paget's disease or rheumatoid arthritis.
Procedures
C57BL/6 mice were treated systemically with osteoprotegerin (OPG) for 15 days or RANKL for 11 days to suppress and stimulate osteoclastogenesis, respectively. The mice were then imaged by positron emission tomography/computed tomography using 64Cu-RGD, followed by determination of serum TRAP5b and bone histology. Standard uptake values were determined to quantify 64Cu-RGD in bones and other tissues.
Results
Mice treated with OPG showed decreased bone uptake of 64Cu-RGD at 1, 2, and 24 h post-injection of the tracer (p < 0.01 for all time points) compared to vehicle controls, which correlated with a post-treatment decrease in serum TRAP5b. In contrast, mice treated with RANKL showed significantly increased bone uptake at 2 h post-injection of 64Cu-RGD (p < 0.05) compared to the vehicle control group, corresponding to increased serum TRAP5b and OC numbers as determined by bone histology.
Conclusions
These data demonstrate that 64Cu-RGD localizes to areas in bone with increased osteoclast numbers and support the use of 64Cu-RGD as an imaging biomarker for osteoclast number that could be used to monitor osteoclast-related pathologies and their treatments.
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References
Kakonen SM, Mundy GR (2003) Mechanisms of osteolytic bone metastases in breast carcinoma. Cancer 97:834–839
Mundy GR (2002) Metastasis to bone: causes, consequences and theraputic opportunities. Nature Rev Cancer 2:584–593
Braun S, Vogl FD, Naume B et al (2005) A pooled analysis of bone marrow micrometastasis in breast cancer. N Engl J Med 353:793–802
Teitelbaum SL (2007) Osteoclasts: what do they do and how do they do it? Am J Pathol 170:427–435
Horton MA, Dorey EL, Nesbitt SA et al (1993) Modulation of vitronectin receptor-mediated osteoclast adhesion by arg-gly-asp peptide analogs: a structure-function analysis. J Bone Miner Res 8:239–247
Horton MA (1997) The alpha v beta 3 integrin “vitronectin receptor”. Int J Biochem Cell Biol 29:721–725
Roodman GD (1997) Mechanisms of bone lesions in multiple myeloma and lymphoma. Cancer 80:1557–1563
Peterson JJ, Kransdorf MJ, O'Connor MI (2003) Diagnosis of occult bone metastases: positron emission tomography. Clin Orthop Relat Res 415S:S120–S128
Hamaoka T, Madewell JE, Podoloff DA, Hortobagyi GN, Ueno NT (2004) Bone imaging in metastatic breast cancer. J Clin Oncol 22:2942–2953
Du Y, Cullum I, Illidge TM, Ell PJ (2007) Fusion of metabolic function and morphology: sequential [18f]fluorodeoxyglucose positron-emission tomography/computed tomography studies yield new insights into the natural history of bone metastases in breast cancer. J Clin Oncol 25:3440–3447
Bjurberg M, Henriksson E, Brun E et al (2009) Early changes in 2-deoxy-2-[18f]fluoro-d-glucose metabolism in squamous-cell carcinoma during chemotherapy in vivo and in vitro. Cancer Biother Radiopharm 24:327–332
Mortimer JE, Dehdashti F, Siegel BA et al (2001) Metabolic flare: indicator of hormone responsiveness in advanced breast cancer. J Clin Oncol 19:2797–2803
Haubner R, Wester HJ, Reuning U et al (1999) Radiolabeled alpha(v)beta3 integrin antagonists: a new class of tracers for tumor targeting. J Nucl Med 40:1061–1071
Sprague JE, Kitaura H, Zou W et al (2007) Noninvasive imaging of osteoclasts in parathyroid hormone-induced osteolysis using a 64cu-labeled rgd peptide. J Nucl Med 48:311–318
Beer AJ, Haubner R, Goebel M et al (2005) Biodistribution and pharmacokinetics of the {alpha}v{beta}3-selective tracer 18f-galacto-rgd in cancer patients. J Nucl Med 46:1333–1341
Beer AJ, Haubner R, Sarbia M et al (2006) Positron emission tomography using [18f]galacto-rgd identifies the level of integrin {alpha}v{beta}3 expression in man. Clin Cancer Res 12:3942–3949
Beer AJ, Haubner R, Wolf I et al (2006) Pet-based human dosimetry of 18f-galacto-rgd, a new radiotracer for imaging alpha v beta3 expression. J Nucl Med 47:763–769
Beer AJ, Schwaiger M (2008) Imaging of integrin alphavbeta3 expression. Cancer Metastasis Rev 27:631–644
Schnell O, Krebs B, Carlsen J et al (2009) Imaging of integrin alpha(v)beta(3) expression in patients with malignant glioma by [18f] galacto-rgd positron emission tomography. Neuro Oncol 11:861–870
Wadas TJ, Deng H, Sprague JE et al (2009) Targeting the alphavbeta3 integrin for small-animal pet/ct of osteolytic bone metastases. J Nucl Med 50:1873–1880
Wadas TJ, Anderson CJ (2006) Radiolabeling of teta- and cb-te2a-conjugated peptides with copper-64. Nat Protoc 1:3062–3068
Qi J, Leahy RM (2000) Resolution and noise properties of map reconstruction for fully 3-d pet. IEEE Trans Med Imaging 19:493–506
Loening AM, Gambhir SS (2003) Amide: a free software tool for multimodality medical image analysis. Mol Imaging 2:131–137
Shidara K, Inaba M, Okuno S et al (2008) Serum levels of trap5b, a new bone resorption marker unaffected by renal dysfunction, as a useful marker of cortical bone loss in hemodialysis patients. Calcif Tissue Int 82:278–287
Kang Y (2004) Breast cancer bone metastasis: molecular basis of tissue tropism. J Musculoskelet Neuronal Interact 4:379–380
Wu Z, McRoberts KS, Theodorescu D (2007) The role of pten in prostate cancer cell tropism to the bone micro-environment. Carcinogenesis 28:1393–1400
Roato I, Gorassini E, Buffoni L et al (2008) Spontaneous osteoclastogenesis is a predictive factor for bone metastases from non-small cell lung cancer. Lung Cancer 61:109–116
Choi Y, Arron JR, Townsend MJ (2009) Promising bone-related therapeutic targets for rheumatoid arthritis. Nat Rev Rheumatol 5:543–548
Chen X, Hou Y, Tohme M et al (2004) Pegylated arg-gly-asp peptide: 64cu labeling and pet imaging of brain tumor alphavbeta3-integrin expression. J Nucl Med 45:1776–1783
Haubner R, Bruchertseifer F, Bock M et al (2004) Synthesis and biological evaluation of a (99m)tc-labelled cyclic rgd peptide for imaging the alphavbeta3 expression. Nuklearmedizin 43:26–32
Hsu AR, Chen X (2008) Advances in anatomic, functional, and molecular imaging of angiogenesis. J Nucl Med 49:511–514
Kyrgidis A, Triaridis S, Vahtsevanos K, Antoniades K (2009) Osteonecrosis of the jaw and bisphosphonate use in breast cancer patients. Expert Rev Anticancer Ther 9:1125–1134
Nakamura H, Hiraga T, Ninomiya T et al (2008) Involvement of cell-cell and cell-matrix interactions in bone destruction induced by metastatic MDA-MB-231 human breast cancer cells in nude mice. J Bone Miner Metab 26:642–647
Pozzi S, Vallet S, Mukherjee S et al (2009) High-dose zoledronic acid impacts bone remodeling with effects on osteoblastic lineage and bone mechanical properties. Clin Cancer Res 15:5829–5839
Walsh NC, Gravallese EM (2004) Bone loss in inflammatory arthritis: mechanisms and treatment strategies. Curr Opin Rheumatol 16:419–427
Lacey DL, Tan HL, Lu J et al (2000) Osteoprotegerin ligand modulates murine osteoclast survival in vitro and in vivo. Am J Pathol 157:435–448
Acknowledgments
This research was funded by NIH grants NRSA F32 CA115148 (TJW), R01 CA097250 (KNW), and P01 CA100730 (KNW) as well as funding from Amgen, Inc.
Conflict of Interest
Dr. Anderson received partial support for the research presented here from Amgen, Inc. Dr. Kostenuik is an employee of Amgen, Inc.
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Zheleznyak, A., Wadas, T.J., Sherman, C.D. et al. Integrin αvβ3 as a PET Imaging Biomarker for Osteoclast Number in Mouse Models of Negative and Positive Osteoclast Regulation. Mol Imaging Biol 14, 500–508 (2012). https://doi.org/10.1007/s11307-011-0512-4
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DOI: https://doi.org/10.1007/s11307-011-0512-4