Get access

Evidence of reciprocal regulation between the high extracellular calcium and RANKL signal transduction pathways in RAW cell derived osteoclasts

Authors

  • Jiake Xu,

    Corresponding author
    1. Molecular Orthopaedic Laboratory, School of Surgery and Pathology, University of Western Australia, Nedlands WA, Australia
    • Molecular Orthopaedics Laboratory, School of Surgery and Pathology, University of Western Australia, QEII Medical Centre, 2nd Floor M Block, Nedlands 6009 WA, Australia.
    Search for more papers by this author
  • Cathy Wang,

    1. Molecular Orthopaedic Laboratory, School of Surgery and Pathology, University of Western Australia, Nedlands WA, Australia
    Search for more papers by this author
  • Renzhi Han,

    1. Molecular Orthopaedic Laboratory, School of Surgery and Pathology, University of Western Australia, Nedlands WA, Australia
    Current affiliation:
    1. Howard Hughes Medical Institute, University of Iowa, College of Medicine, 400 EMRB, Iowa City, IA 52242.
    Search for more papers by this author
  • Nathan Pavlos,

    1. Molecular Orthopaedic Laboratory, School of Surgery and Pathology, University of Western Australia, Nedlands WA, Australia
    Search for more papers by this author
  • Tony Phan,

    1. Molecular Orthopaedic Laboratory, School of Surgery and Pathology, University of Western Australia, Nedlands WA, Australia
    Search for more papers by this author
  • James H. Steer,

    1. Pharmacology Unit, School of Medicine and Pharmacology, University of Western Australia, Nedlands WA, Australia
    Search for more papers by this author
  • Anthony J. Bakker,

    1. Physiology Unit, School of Biomedical and Chemical Sciences, University of Western Australia, Nedlands WA, Australia
    Search for more papers by this author
  • David A. Joyce,

    1. Pharmacology Unit, School of Medicine and Pharmacology, University of Western Australia, Nedlands WA, Australia
    Search for more papers by this author
  • Ming H. Zheng

    1. Molecular Orthopaedic Laboratory, School of Surgery and Pathology, University of Western Australia, Nedlands WA, Australia
    Search for more papers by this author

Abstract

During bone resorption, osteoclasts are exposed to high Ca2+ concentrations (up to 40 mM). The role of high extracellular Ca2+ in receptor activator of NF-κB ligand (RANKL)-mediated osteoclast survival and their functional interrelationship is unclear. In this study, we show that RANKL enhances osteoclast tolerance to high extracellular Ca2+ by protecting the cell from cell death in a dose dependent manner. We have provided evidence that RANKL does this by attenuating high extracellular Ca2+-induced Ca2+ elevations. Moreover, we have found that high extracellular Ca2+-induced cell death was partially inhibited by a caspase-3 inhibitor, suggesting caspase-3-mediated apoptosis is involved. Conversely, using reporter gene assays and Western blot analysis, we have demonstrated that high extracellular Ca2+ desensitizes the RANKL-induced activation of NF-κB and c-Jun N-terminal kinase (JNK), and inhibits constitutive and RANKL-stimulated ERK phosphorylation, indicating a negative feed-back mechanism via specific RANKL signaling pathways. Taken together, this study provides evidence for a reciprocal regulation between high extracellular Ca2+ and RANKL signaling in RAW cell derived osteoclasts. Our data imply a cross talk mechanism of extracellular Ca2+ on osteoclast survival through the regulation of RANKL. © 2004 Wiley-Liss, Inc.

Ancillary