The Phosphoinositide 3-Kinase Isoform PI3Kβ Regulates Osteoclast-Mediated Bone Resorption in Humans and Mice

Authors

  • Dávid Győri,

    1. Semmelweis University School of Medicine, and MTA-SE “Lendület” Inflammation Physiology Research Group of the Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary
    Search for more papers by this author
  • Dániel Csete,

    1. Semmelweis University School of Medicine, and MTA-SE “Lendület” Inflammation Physiology Research Group of the Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary
    Search for more papers by this author
  • Szilvia Benkő,

    1. University of Debrecen, Debrecen, Hungary
    Search for more papers by this author
  • Suhasini Kulkarni,

    1. Babraham Institute, Cambridge, UK
    Search for more papers by this author
  • Péter Mandl,

    1. Medical University of Vienna, Vienna, Austria
    Search for more papers by this author
  • Csaba Dobó-Nagy,

    1. Semmelweis University School of Dentistry, Budapest, Hungary
    Search for more papers by this author
  • Bart Vanhaesebroeck,

    1. Queen Mary University of London, London, UK
    Search for more papers by this author
    • Dr. Vanhaesebroeck has received consulting fees, speaking fees, and/or honoraria from Karus Therapeutics and Intellikine/Millenium, the Takeda Oncology Company (less than $10,000 each) and from Activiomics (more than $10,000), owns stock or stock options in Activiomics, and has submitted patent applications for phosphoproteomics and new phosphoinositide 3-kinase drug targets.

  • Len Stephens,

    1. Babraham Institute, Cambridge, UK
    Search for more papers by this author
    • Drs. Stephens and Hawkins have received consulting fees, speaking fees, and/or honoraria from Karus Therapeutics and GlaxoSmithKline (less than $10,000 each);

  • Phillip T. Hawkins,

    1. Babraham Institute, Cambridge, UK
    Search for more papers by this author
    • Drs. Stephens and Hawkins have received consulting fees, speaking fees, and/or honoraria from Karus Therapeutics and GlaxoSmithKline (less than $10,000 each);

    • Dr. Hawkins also owns stock in Karus Therapeutics.

  • Attila Mócsai

    Corresponding author
    1. Semmelweis University School of Medicine, and MTA-SE “Lendület” Inflammation Physiology Research Group of the Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary
    Search for more papers by this author

Abstract

Objective

While phosphoinositide 3-kinases (PI3Ks) are involved in various intracellular signal transduction processes, the specific functions of the different PI3K isoforms are poorly understood. We have previously shown that the PI3Kβ isoform is required for arthritis development in the K/BxN serum–transfer model. Since osteoclasts play a critical role in pathologic bone loss during inflammatory arthritis and other diseases, we undertook this study to test the role of PI3Kβ in osteoclast development and function using a combined genetic and pharmacologic approach.

Methods

The role of PI3Kβ in primary human and murine osteoclast cultures was tested with the PI3Kβ-selective inhibitor TGX221 and by using PI3Kβ−/− mice. The trabecular bone architecture of PI3Kβ−/− mice was evaluated using micro–computed tomography and histomorphometric analyses.

Results

The expression of PI3Kβ was strongly and specifically up-regulated during in vitro osteoclast differentiation. In vitro development of large multinucleated osteoclasts from human or murine progenitors and their resorption capacity were strongly reduced by the PI3Kβ inhibitor TGX221 or by the genetic deficiency of PI3Kβ. This was likely due to defective cytoskeletal reorganization and vesicular trafficking, since PI3Kβ−/− mouse multinucleated cells failed to form actin rings and retained intracellular acidic vesicles and cathepsin K. In contrast, osteoclast-specific gene expression and the survival and apoptosis of osteoclasts were not affected. PI3Kβ−/− mice had significantly increased trabecular bone volume and showed abnormal osteoclast morphology with defective resorption pit formation.

Conclusion

PI3Kβ plays an important role in osteoclast development and function and is required for in vivo bone homeostasis.

Ancillary