The C-Terminal Domain of Chondroadherin: A New Regulator of Osteoclast Motility Counteracting Bone Loss

Authors

  • Mattia Capulli,

    1. Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
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  • Ole K Olstad,

    1. Department of Clinical Chemistry, Ullevaal University Hospital and Institute of Medical Biochemistry, University of Oslo, Oslo, Norway
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  • Patrik Önnerfjord,

    1. Department of Clinical Sciences, Section of Rheumatology, Lund University, Lund, Sweden
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  • Viveka Tillgren,

    1. Department of Clinical Sciences, Section of Rheumatology, Lund University, Lund, Sweden
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  • Maurizio Muraca,

    1. Ospedale Pediatrico Bambino Gesù, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
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  • Kaare M Gautvik,

    1. Department of Clinical Chemistry, Ullevaal University Hospital and Institute of Medical Biochemistry, University of Oslo, Oslo, Norway
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  • Dick Heinegård,

    1. Department of Clinical Sciences, Section of Rheumatology, Lund University, Lund, Sweden
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    •   This article is dedicated to Professor Dick Heinegård, who died prematurely after having contributed largely to this work and approving the manuscript.
  • Nadia Rucci,

    Corresponding author
    1. Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
    • Address correspondence to: Nadia Rucci, PhD, Department of Biotechnological and Applied Clinical Sciences, Via Vetoio – Coppito 2, 67100 L'Aquila, Italy. E-mail: rucci@univaq.it

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  • Anna Teti

    1. Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
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    • * NR and AT contributed equally to this work.

ABSTRACT

Chondroadherin (CHAD) is a leucine-rich protein promoting cell attachment through binding to integrin α2β1 and syndecans. We observed that CHAD mRNA and protein were lower in bone biopsies of 50-year-old to 65-year-old osteoporotic women and in bone samples of ovariectomized mice versus gender/age–matched controls, suggesting a role in bone metabolism. By the means of an internal cyclic peptide (cyclicCHAD), we observed that its integrin binding sequence impaired preosteoclast migration through a nitric oxide synthase 2–dependent mechanism, decreasing osteoclastogenesis and bone resorption in a concentration-dependent fashion, whereas it had no effect on osteoblasts. Consistently, cyclicCHAD reduced transcription of two nitric oxide downstream genes, migfilin and vasp, involved in cell motility. Furthermore, the nitric oxide donor, S-nitroso-N-acetyl-D,L-penicillamine, stimulated preosteoclast migration and prevented the inhibitory effect of cyclicCHAD. Conversely, the nitric oxide synthase 2 (NOS2) inhibitor, N5-(1-iminoethyl)-l-ornithine, decreased both preosteoclast migration and differentiation, confirming a role of the nitric oxide pathway in the mechanism of action triggered by cyclicCHAD. In vivo, administration of cyclicCHAD was well tolerated and increased bone volume in healthy mice, with no adverse effect. In ovariectomized mice cyclicCHAD improved bone mass by both a preventive and a curative treatment protocol, with an effect in line with that of the bisphosphonate alendronate, that was mimicked by the NOS2 inhibitor [L-N6-(1-Iminoethyl)-lysine.2 dihydrochloride]. In both mouse models, cyclicCHAD reduced osteoclast and bone resorption without affecting osteoblast parameters and bone formation. In conclusion, CHAD is a novel regulator of bone metabolism that, through its integrin binding domain, inhibits preosteoclast motility and bone resorption, with a potential translational impact for the treatment of osteoporosis. © 2014 American Society for Bone and Mineral Research.

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