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The intact strontium ranelate complex stimulates osteoblastogenesis and suppresses osteoclastogenesis by antagonizing NF-κB activation

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Abstract

Strontium ranelate, a pharmaceutical agent shown in clinical trials to be effective in managing osteoporosis and reducing fracture risk in postmenopausal women, is relatively unique in its ability to both blunt bone resorption and stimulate bone formation. However, its mechanisms of action are largely unknown. As the nuclear factor-kappa B (NF-κB) activation antagonists both stimulate osteoblastic bone formation and repress osteoclastic bone resorption, we hypothesized that strontium ranelate may achieve its anabolic and anti-catabolic activities by modulating NF-κB activation in bone cells. In this study, osteoclast and osteoblast precursors were treated with intact strontium ranelate or its individual components sodium ranelate and/or strontium chloride, and its effect on in vitro osteoclastogenesis and osteoblastogenesis and on NF-κB activation quantified. Although the activity of strontium ranelate has been attributed to the release of strontium ions, low dose intact strontium ranelate complex, but not sodium ranelate and/or strontium chloride, potently antagonized NF-κB activation in osteoclasts and osteoblasts in vitro, and promoted osteoblast differentiation while suppressing osteoclast formation. Taken together, our data suggest a novel centralized mechanism by which strontium ranelate promotes osteoblast activity and suppresses osteoclastogenesis, based on suppression of NF-κB signal transduction. We further demonstrate that the biological actions of strontium ranelate may be related to low dose of the intact molecule rather than dissociation and release of strontium ions, as previously thought. These data may facilitate the development of additional novel pharmacological agents for the amelioration of osteoporosis, based on NF-κB blockade.

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Acknowledgments

M. Neale Weitzmann is supported in part by National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) Grants AR059364, AR053607 and AR056090 and by the Biomedical Laboratory Research and Development Service of the Veterans Affairs Office of Research and Development Grant 5I01BX000105.

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Correspondence to Masayoshi Yamaguchi or M. Neale Weitzmann.

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M. Yamaguchi and M. Neale Weitzmann have contributed equally.

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Yamaguchi, M., Neale Weitzmann, M. The intact strontium ranelate complex stimulates osteoblastogenesis and suppresses osteoclastogenesis by antagonizing NF-κB activation. Mol Cell Biochem 359, 399–407 (2012). https://doi.org/10.1007/s11010-011-1034-8

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  • DOI: https://doi.org/10.1007/s11010-011-1034-8

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