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Effects of the RANKL inhibitor, osteoprotegerin, on the pain and histopathology of bone cancer in rats

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Abstract

Background

This study investigated the effects of the receptor activator for nuclear factor κB ligand (RANKL) inhibitor, osteoprotegerin (OPG), on tumor-induced allodynia, osteolysis, and bone histology in the mammary tumor (MRMT-1) rat model for bone cancer pain.

Methods

Rats (n = 8/group) were inoculated with MRMT-1 or culture medium in the proximal right tibia, injected with OPG or vehicle subcutaneously 2–3 times weekly, evaluated for mechanical allodynia with von Frey paw stimulation, and euthanized on Day 20 for necropsy. Three groups were evaluated starting on Day 5 and received the following interventions beginning on Day 1: tumor and OPG, tumor and vehicle, or culture medium and vehicle. Three additional groups received the same interventions but were evaluated starting on Day 3. A seventh group started OPG on Day 8 after tumor inoculation.

Results

Starting OPG on Day 1 reduced allodynia significantly compared with vehicle injections; pain relief was observed within 5–6 days after tumor inoculation and lasted throughout follow-up. Starting OPG on Day 8 did not reverse allodynia significantly compared with the tumor control group. Regardless of treatment start time, OPG treatment reduced osteoclast number and tartrate-resistant acid phosphatase levels, increased bone mineral density, preserved normal bone volume and integrity on micro-computed tomography, reduced relative tumor volume in the bone, and reduced staining for glial fibrillary acidic protein in the spinal cord.

Conclusions

RANKL inhibition with OPG reduced bone resorption and bone pain in rats with malignant bone disease; further study is warranted to determine if RANKL inhibition has similar benefits in humans.

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Abbreviations

ANOVA:

Analysis of variance

BMD:

Bone mineral density

DXA:

Dual X-ray absorptiometry

GFAP:

Glial fibrillary acidic protein

MicroCT:

Micro-computed tomography

MRMT-1:

Rat mammary tumor cell line

OPG:

Osteoprotegerin

RANK:

Receptor activator for nuclear factor κB

RANKL:

Receptor activator for nuclear factor κB ligand

sTRAP5b:

Tartrate-resistant acid phosphatase form 5b

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Acknowledgments

This study was supported by a grant from Amgen, Inc. At the time of the study, William C. Dougall was an employee of Amgen, Inc., which is researching and developing an anti-RANKL monoclonal antibody for clinical use, and Martine Roudier and Steve Bain were employees of SkeleTech, Inc., which received a grant from Amgen, Inc. to perform the study. Chung Liu, Hellen Zheng, and Eric Bell provided technical assistance. Jonathan N. Latham and Christine Gatchalian provided editorial assistance with the manuscript.

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Authors and Affiliations

  1. SkeleTech, Inc., Bothell, WA, USA

    Martine P. Roudier & Steven D. Bain

  2. Department of Cancer Biology, Amgen Washington, Seattle, WA, USA

    William C. Dougall

  3. Department of Pathology, Amgen Washington, 1201 Amgen Court West, Seattle, WA , 98119-3105, USA

    Martine P. Roudier

Authors
  1. Martine P. Roudier
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  2. Steven D. Bain
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  3. William C. Dougall
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Correspondence to Martine P. Roudier.

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Roudier, M.P., Bain, S.D. & Dougall, W.C. Effects of the RANKL inhibitor, osteoprotegerin, on the pain and histopathology of bone cancer in rats. Clin Exp Metastasis 23, 167–175 (2006). https://doi.org/10.1007/s10585-006-9026-x

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  • DOI: https://doi.org/10.1007/s10585-006-9026-x

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