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The Role of Calcium and Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP) in Human Osteoclast Formation and Resorption

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Abstract

Osteoclasts are specialised bone resorbing cells which form by fusion of circulating mononuclear phagocyte precursors. Bone resorption results in the release of large amounts of calcium into the extracellular fluid (ECF), but it is not certain whether changes in extracellular calcium concentration [Ca2+]e influence osteoclast formation and resorption. In this study, we sought to determine the effect of [Ca2+]e and NAADP, a potent calcium mobilising messenger that induces calcium uptake, on human osteoclast formation and resorption. CD14+ human monocytes were cultured with M-CSF and RANKL in the presence of different concentrations of calcium and NAADP and the effect on osteoclast formation and resorption evaluated. We found that the number of TRAP+ multinucleated cells and the extent of lacunar resorption were reduced when there was an increase in extracellular calcium and NAADP. This was associated with a decrease in RANK mRNA expression by CD14+ cells. At high concentrations (20 mM) of [Ca2+]e mature osteoclast resorption activity remained unaltered relative to control cultures. Our findings indicate that osteoclast formation is inhibited by a rise in [Ca2+]e and that RANK expression by mononuclear phagocyte osteoclast precursors is also [Ca2+]e dependent. Changes in NAADP also influence osteoclast formation, suggesting a role for this molecule in calcium handling. Osteoclasts remained capable of lacunar resorption, even at high ECF [Ca2+]e, in keeping with their role in physiological and pathological bone resorption.

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Acknowledgments

Research was supported through funding from the EuroBoNet consortium, Oxford NIHR Biomedical Research Unit, the Rosetrees Trust, Sarcoma (UK) and the Bone Cancer Research Trust. The Structural Genomics Consortium is a registered charity (No. 1097737) that receives funds from Abbvie, Bayer Healthcare, Boehringer Ingelheim, the Canadian Institutes for Health Research, the Canadian Foundation for Innovation, Eli Lilly and Company, Genome Canada, GlaxoSmithKline, the Ontario Ministry of Economic Development and Innovation, Janssen, the Novartis Research Foundation, Pfizer, Takeda, and the Wellcome Trust.

Conflict of interest

X. Cheng, E. S. Hookway, T. Kashima, U. Oppermann, A. Galione and N. A. Athanasou declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

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Authors and Affiliations

  1. Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Nuffield Orthopaedic Centre, University of Oxford, Oxford, OX3 7LD, UK

    X. Cheng, E. S. Hookway, T. Kashima, U. Oppermann & N. A. Athanasou

  2. Structural Genomics Consortium, University of Oxford, Old Road Campus, Roosevelt Drive, Headington, OX3 7DQ, UK

    U. Oppermann

  3. Department of Pharmacology, University of Oxford, Oxford, OX1 3QT, UK

    A. Galione

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  1. X. Cheng
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  2. E. S. Hookway
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  3. T. Kashima
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  4. U. Oppermann
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  5. A. Galione
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  6. N. A. Athanasou
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Correspondence to N. A. Athanasou.

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Cheng, X., Hookway, E.S., Kashima, T. et al. The Role of Calcium and Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP) in Human Osteoclast Formation and Resorption. Calcif Tissue Int 96, 73–79 (2015). https://doi.org/10.1007/s00223-014-9939-3

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  • DOI: https://doi.org/10.1007/s00223-014-9939-3

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