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This article is part of the supplement: Proceedings of the 8th Global Arthritis Research Network (GARN) Meeting and 1st Bio-Rheumatology International Congress (BRIC)

Oral presentation

Regulation of bone mass at unloaded condition by osteocyte network

Toshihisa Komori

  • Correspondence: Toshihisa Komori

Author Affiliations

Department of Cell Biology, Unit of Basic Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8588, Japan

Arthritis Research & Therapy 2012, 14(Suppl 1):O13  doi:10.1186/ar3568


The electronic version of this article is the complete one and can be found online at: http://arthritis-research.com/content/14/S1/O13


Published:9 February 2012

© 2012 Komori; licensee BioMed Central Ltd.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Oral presentation

Disuse osteoporosis, which occurs commonly in prolonged bed rest and immobilization, is becoming a major problem in modern societies; however, the molecular mechanisms underlying unloading-driven bone loss have not been fully elucidated. Bone adjusts its shape and strength against mechanical stress. Osteocytes are the most abundant cells in bone and comprise the communication system through the processes and canaliculi throughout bone. The osteocyte network is considered to be an ideal mechanosensor and mechanotransduction system. We found that overexpression of BCL2 in osteoblasts reduces the number of osteocyte processes, probably due to the function of Bcl2 that modulates cytoskeletal reorganization, and induces the apoptosis of osteocytes, in which the transgene expression was reduced, presumably caused by an insufficient supply of oxygen, nutrients, and survival factors due to the reduced osteocyte processes. Our BCL2 transgenic mouse with accumulated dead osteocytes is a useful model to analyze the function of osteocytes, because a repair process, which replaces dead osteocytes with new osteocytes by bone resorption and formation, was not evident in the mice irrespective of the massive accumulation of dead osteocytes

We searched for the molecules responsible for disuse osteoporosis using BCL2 transgenic mice. Pyruvate dehydrogenase kinase isozymes (Pdk1, Pdk2, Pdk3, and Pdk4) are negative regulators of pyruvate dehydrogenase complex (PDC), which converts pyruvate to acetyl-CoA in the mitochondria, linking glycolysis to the energetic and anabolic functions of the tricarboxylic acid (TCA) cycle. Pdk4 was upregulated in femurs and tibiae of wild-type mice but not of BCL2 transgenic mice after tail suspension. Bone in Pdk4-/- mice developed normally and was maintained. At unloading, however, bone mass was reduced due to enhanced osteoclastogenesis and Rankl expression in wild-type mice but not in Pdk4-/- mice. Osteoclast differentiation of Pdk4-/- bone marrow-derived monocyte/macrophage lineage cells (BMMs) in the presence of M-CSF and RANKL was suppressed, and osteoclastogenesis was impaired in the coculture of wild-type BMMs and Pdk4-/- osteoblasts, in which Rankl expression and promoter activity were reduced. Further, introduction of Pdk4 into Pdk4-/- BMMs and osteoblasts enhanced osteoclastogenesis and Rankl expression and activated Rankl promoter. These findings indicate that upregulation of Pdk4 expression in osteoblasts and bone marrow cells after unloading is, at least in part, responsible for the enhancement of osteoclastogenesis and bone resorption after unloading [1].

References

  1. Wang Y, Liu W, Masuyama R, Fukuyama R, Ito M, Zhang Q, Komori H, Murakami T, Moriishi T, Miyazaki T, Kitazawa R, Yoshida CA, Kawai Y, Izumi S, Komori T: Pyruvate dehydrogenase kinase 4 induces bone loss at unloading by promoting osteoclastogenesis.

    Bone 2012, 50:409-419. PubMed Abstract | Publisher Full Text OpenURL