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.
The Phosphoinositide 3-Kinase Isoform PI3Kβ Regulates Osteoclast-Mediated Bone Resorption in Humans and Mice
Article first published online: 28 JUL 2014
© 2014 The Authors. Arthritis & Rheumatology is published by Wiley Periodicals, Inc. on behalf of the American College of Rheumatology.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Arthritis & Rheumatology
Volume 66, Issue 8, pages 2210–2221, August 2014
How to Cite
Győri, D., Csete, D., Benkő, S., Kulkarni, S., Mandl, P., Dobó-Nagy, C., Vanhaesebroeck, B., Stephens, L., Hawkins, P. T. and Mócsai, A. (2014), The Phosphoinositide 3-Kinase Isoform PI3Kβ Regulates Osteoclast-Mediated Bone Resorption in Humans and Mice. Arthritis & Rheumatology, 66: 2210–2221. doi: 10.1002/art.38660
- Issue published online: 28 JUL 2014
- Article first published online: 28 JUL 2014
- Accepted manuscript online: 9 APR 2014 12:00AM EST
- Manuscript Accepted: 3 APR 2014
- Manuscript Received: 8 OCT 2013
- Hungarian Scientific Research Fund. Grant Number: OTKA F-68782
- Ludwig Institute for Cancer Research
- Wellcome Trust. Grant Number: WT085889MA
- UK Biotechnology and Biological Sciences Research Council. Grant Numbers: BB/DO13593/1, BBS/B/01979
- European Research Council (Starting Independent Investigator Award). Grant Number: 206283
- European Union Seventh Framework Programme (project TARKINAID; Cooperation Program). Grant Number: 282095
- Lendület Programme of the Hungarian Academy of Sciences. Grant Number: LP2013-66/2013
- EMBO Short-Term Fellowship
- European Molecular Biology Organization
- Zoltán Magyary Postdoctoral Fellowship
- C. J. Martin Fellowship awarded by the National Heart Foundation (Australia)
- National Health and Medical Research Council (Australia)
- Wellcome Trust. Grant Number: 087782
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.
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.
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.
PI3Kβ plays an important role in osteoclast development and function and is required for in vivo bone homeostasis.