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Skeletal deterioration induced by RANKL infusion: a model for high-turnover bone disease

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Abstract

Summary

RANKL was administered continuously to rats for 28 days to investigate its potential as a disease model for the skeletal system. Bone turnover rates, bone material, structural and mechanical properties were evaluated. RANKL infusion caused overall skeletal complications comparable to those in high bone-turnover conditions, such as postmenopausal osteoporosis.

Introduction

RANKL is an essential mediator for osteoclast development. No study has examined in detail the direct skeletal consequences of excess RANKL on bone turnover, mineralization, architecture, and vascular calcification. We, therefore, administrated soluble RANKL continuously into mature rats and created a bone-loss model.

Methods

Six-month-old Sprague-Dawley (SD) rats were assigned to three groups (n = 12) receiving continuous administration of saline (VEH) or human RANKL (35 μg/kg/day, LOW or 175 μg/kg/day, HI) for 28 days. Blood was collected routinely during the study. At sacrifice, hind limbs and aorta were removed and samples were analyzed.

Results

High dose RANKL markedly stimulated serum osteocalcin and TRAP-5b levels and reduced femur cortical bone volume (−7.6%) and trabecular volume fraction (BV/TV) at the proximal tibia (−64% vs. VEH). Bone quality was significantly degraded in HI, as evidenced by decreased femoral percent mineralization, trabecular connectivity, and increased endocortical bone resorption perimeters. Both cortical and trabecular bone mechanical properties were reduced by high dose RANKL. No differences were observed in the mineral content of the abdominal aorta.

Conclusions

Continuous RANKL infusion caused general detrimental effects on rat skeleton. These changes are comparable to those commonly observed in high-turnover bone diseases such as postmenopausal osteoporosis.

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Acknowledgments

This work was supported by the National Space Biomedical Research Institute through NASA NCC 9–58, Amgen, Inc., and BioServe Space Technologies (through NASA NCC8–242). The authors are grateful to Nessa Hawkins and Brian Williamson (Amgen) for producing and purifying recombinant RANKL. The editorial and formatting assistance of Jenny Bourne is greatly appreciated.

Conflicts of interest

Drs. Kostenuik, Ominsky, Asuncion, Morony and Adamu are employees and stockholders of Amgen Inc.; Dr. Bateman receives grant support from Amgen.

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Authors and Affiliations

  1. Department of Bioengineering, Clemson University, 501 Rhodes Research Center, Clemson, SC, 29634, USA

    Y. Y. Yuan, D. T. Simionescu, D. M. Basalyga & T. A. Bateman

  2. Metabolic Disorders, Amgen Inc., Thousand Oaks, CA, USA

    P. J. Kostenuik, M. S. Ominsky, S. Morony, S. Adamu & F. J. Asuncion

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  1. Y. Y. Yuan
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  2. P. J. Kostenuik
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  3. M. S. Ominsky
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  4. S. Morony
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  5. S. Adamu
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  9. T. A. Bateman
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Correspondence to T. A. Bateman.

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Yuan, Y.Y., Kostenuik, P.J., Ominsky, M.S. et al. Skeletal deterioration induced by RANKL infusion: a model for high-turnover bone disease. Osteoporos Int 19, 625–635 (2008). https://doi.org/10.1007/s00198-007-0509-7

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  • DOI: https://doi.org/10.1007/s00198-007-0509-7

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