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Strontium ranelate treatment of human primary osteoblasts promotes an osteocyte-like phenotype while eliciting an osteoprotegerin response

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Abstract

Summary

The effect of strontium ranelate (SR) on human osteoblast differentiation was tested. SR induced osteoblastic proliferation, in vitro mineralization, and increased the expression of osteocyte markers. SR also elicited an osteoprotegerin (OPG) secretory response. We conclude that SR promotes the osteoblast maturation and osteocyte differentiation while promoting an additional antiresorptive effect.

Introduction

SR is a new treatment for osteoporosis that reduces the risk of hip and vertebral fractures in postmenopausal women. This study sought to investigate the extent, to which SR modulates human osteoblast differentiation.

Methods

Adult human primary osteoblasts (NHBC) were exposed to SR under mineralizing conditions in long-term cultures. Osteoblast differentiation status was investigated by cell-surface phenotypic analysis. Expression of genes associated with osteoblast/osteocyte differentiation was examined using real-time RT-PCR. Secreted OPG was assayed by enzyme-linked immunosorbent assay.

Results

SR significantly increased osteoblast replication. SR time- and dose-dependently induced an osteocyte-like phenotype, as determined by cell surface alkaline phosphatase and STRO-1 expression. SR at 5 mM or greater dramatically increased in vitro mineralization. In parallel, mRNA levels of dentin matrix protein (DMP)-1 and sclerostin were higher under SR treatment, strongly suggestive of the presence of osteocytes. SR also increased the OPG/RANKL ratio throughout the culture period, consistent with an effect to inhibit osteoblast-induced osteoclastogenesis.

Conclusions

This study suggests that SR can promote osteoblast maturation and an osteocyte-like phenotype. Coupled with its effect on the OPG/RANKL system, these findings are consistent with in vivo effects in patients receiving SR for the treatment of osteoporosis.

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Acknowledgements

This study was funded in part by Servier, Courbevoie, France. This work was also supported by the National Health and Medical Research Council of Australia (NHMRC). GJA was supported by a NHMRC R Douglas Wright Fellowship and by Osteoporosis Australia. The authors are grateful to the surgeons and nursing staff of the Department of Orthopaedics and Trauma of the Royal Adelaide Hospital for their kind assistance in the provision of bone samples at surgery.

Conflicts of interest

This study was funded in part by Servier. PH is an employee of Servier. The authors state that they had full access to all of the data in the study. By so doing, they accept complete responsibility for the integrity of the data and the accuracy of the data analysis.

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Authors and Affiliations

  1. Bone Cell Biology Group, Discipline of Orthopaedics and Trauma, University of Adelaide and Hanson Institute, Adelaide, Australia

    G. J. Atkins, K. J. Welldon & D. M. Findlay

  2. Servier, Courbevoie, France

    P. Halbout

  3. Discipline of Orthopaedics and Trauma, University of Adelaide, Level 4, Bice Building, Royal Adelaide Hospital, North Terrace, Adelaide, 5000, Australia

    G. J. Atkins

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  1. G. J. Atkins
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Correspondence to G. J. Atkins.

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Atkins, G.J., Welldon, K.J., Halbout, P. et al. Strontium ranelate treatment of human primary osteoblasts promotes an osteocyte-like phenotype while eliciting an osteoprotegerin response. Osteoporos Int 20, 653–664 (2009). https://doi.org/10.1007/s00198-008-0728-6

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