Skip to main content

Advertisement

SpringerLink
Log in

Integrin αvβ3 as a PET Imaging Biomarker for Osteoclast Number in Mouse Models of Negative and Positive Osteoclast Regulation

  • Research Article
  • Published:
Molecular Imaging and Biology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Kakonen SM, Mundy GR (2003) Mechanisms of osteolytic bone metastases in breast carcinoma. Cancer 97:834–839

    Article  PubMed  Google Scholar 

  2. Mundy GR (2002) Metastasis to bone: causes, consequences and theraputic opportunities. Nature Rev Cancer 2:584–593

    Article  CAS  Google Scholar 

  3. 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

    Article  PubMed  CAS  Google Scholar 

  4. Teitelbaum SL (2007) Osteoclasts: what do they do and how do they do it? Am J Pathol 170:427–435

    Article  PubMed  CAS  Google Scholar 

  5. 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

    Article  PubMed  CAS  Google Scholar 

  6. Horton MA (1997) The alpha v beta 3 integrin “vitronectin receptor”. Int J Biochem Cell Biol 29:721–725

    Article  PubMed  CAS  Google Scholar 

  7. Roodman GD (1997) Mechanisms of bone lesions in multiple myeloma and lymphoma. Cancer 80:1557–1563

    Article  PubMed  CAS  Google Scholar 

  8. Peterson JJ, Kransdorf MJ, O'Connor MI (2003) Diagnosis of occult bone metastases: positron emission tomography. Clin Orthop Relat Res 415S:S120–S128

    Article  Google Scholar 

  9. Hamaoka T, Madewell JE, Podoloff DA, Hortobagyi GN, Ueno NT (2004) Bone imaging in metastatic breast cancer. J Clin Oncol 22:2942–2953

    Article  PubMed  Google Scholar 

  10. 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

    Article  PubMed  Google Scholar 

  11. 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

    Article  PubMed  CAS  Google Scholar 

  12. 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

    PubMed  CAS  Google Scholar 

  13. 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

    PubMed  CAS  Google Scholar 

  14. 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

    PubMed  CAS  Google Scholar 

  15. 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

    PubMed  CAS  Google Scholar 

  16. 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

    Article  PubMed  CAS  Google Scholar 

  17. 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

    PubMed  CAS  Google Scholar 

  18. Beer AJ, Schwaiger M (2008) Imaging of integrin alphavbeta3 expression. Cancer Metastasis Rev 27:631–644

    Article  PubMed  CAS  Google Scholar 

  19. 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

    Article  PubMed  Google Scholar 

  20. 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

    Article  PubMed  CAS  Google Scholar 

  21. Wadas TJ, Anderson CJ (2006) Radiolabeling of teta- and cb-te2a-conjugated peptides with copper-64. Nat Protoc 1:3062–3068

    Article  PubMed  CAS  Google Scholar 

  22. Qi J, Leahy RM (2000) Resolution and noise properties of map reconstruction for fully 3-d pet. IEEE Trans Med Imaging 19:493–506

    Article  PubMed  CAS  Google Scholar 

  23. Loening AM, Gambhir SS (2003) Amide: a free software tool for multimodality medical image analysis. Mol Imaging 2:131–137

    Article  PubMed  Google Scholar 

  24. 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

    Article  PubMed  CAS  Google Scholar 

  25. Kang Y (2004) Breast cancer bone metastasis: molecular basis of tissue tropism. J Musculoskelet Neuronal Interact 4:379–380

    PubMed  CAS  Google Scholar 

  26. 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

    Article  PubMed  CAS  Google Scholar 

  27. 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

    Article  PubMed  CAS  Google Scholar 

  28. Choi Y, Arron JR, Townsend MJ (2009) Promising bone-related therapeutic targets for rheumatoid arthritis. Nat Rev Rheumatol 5:543–548

    Article  PubMed  CAS  Google Scholar 

  29. 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

    PubMed  CAS  Google Scholar 

  30. 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

    PubMed  CAS  Google Scholar 

  31. Hsu AR, Chen X (2008) Advances in anatomic, functional, and molecular imaging of angiogenesis. J Nucl Med 49:511–514

    Article  PubMed  Google Scholar 

  32. 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

    Article  PubMed  CAS  Google Scholar 

  33. 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

    Article  PubMed  CAS  Google Scholar 

  34. 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

    Article  PubMed  CAS  Google Scholar 

  35. Walsh NC, Gravallese EM (2004) Bone loss in inflammatory arthritis: mechanisms and treatment strategies. Curr Opin Rheumatol 16:419–427

    Article  PubMed  Google Scholar 

  36. 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

    Article  PubMed  CAS  Google Scholar 

Download references

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.

Author information

Author notes

  1. Thaddeus J. Wadas

    Present address: Department of Cancer Biology, Wake Forest University, Winston-Salem, NC, USA

  2. Carolyn J. Anderson

    Present address: Department of Radiology, University of Pittsburgh, 100 Technology Drive; Suite 452, Pittsburgh, PA, 15219, USA

Authors and Affiliations

  1. Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, USA

    Alexander Zheleznyak, Thaddeus J. Wadas, Christopher D. Sherman, Jessica M. Wilson & Carolyn J. Anderson

  2. Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA

    Katherine N. Weilbaecher

  3. Department of Biochemistry & Molecular Biophysics, Washington University School of Medicine, St. Louis, MO, USA

    Carolyn J. Anderson

  4. Department of Chemistry, Washington University, St. Louis, MO, USA

    Carolyn J. Anderson

  5. Department of Metabolic Disorders, Amgen, Inc., Thousand Oaks, CA, USA

    Paul J. Kostenuik

Authors
  1. Alexander Zheleznyak
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Thaddeus J. Wadas
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Christopher D. Sherman
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jessica M. Wilson
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Paul J. Kostenuik
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Katherine N. Weilbaecher
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Carolyn J. Anderson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Carolyn J. Anderson.

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11307-011-0512-4

Key words

Search

Navigation