Spatial Distribution of Bax and Bcl-2 in Osteocytes After Bone Fatigue: Complementary Roles in Bone Remodeling Regulation?

Authors

  • Olivier Verborgt,

    1. Leni and Peter W. May Department of Orthopedics, Mount Sinai School of Medicine, New York, NY, USA
    2. Department of Orthopedics and Traumatology, University of Antwerp, Antwerp, Belgium
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  • Nadine A. Tatton,

    1. Department of Neurology, Mount Sinai School of Medicine, New York, NY, USA
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  • Robert J. Majeska,

    1. Leni and Peter W. May Department of Orthopedics, Mount Sinai School of Medicine, New York, NY, USA
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  • Mitchell B. Schaffler Ph.D.

    Corresponding author
    1. Leni and Peter W. May Department of Orthopedics, Mount Sinai School of Medicine, New York, NY, USA
    • Leni and Peter W. May Department of Orthopaedics, Box 1188, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA
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  • The authors have no conflict of interest

Abstract

Osteocyte apoptosis appears to play a key role in the mechanism by which osteoclastic resorption activity targets bone for removal, because osteocyte apoptosis occurs in highly specific association with microdamage and subsequent remodeling after fatigue. However, beyond terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP)-biotin nick end labeling (TUNEL) assay, little is known about the mechanisms controlling osteocyte apoptosis in vivo. In the current studies, expression of Bax, a proapoptotic gene product, and Bcl-2, an antiapoptotic gene product, was determined in osteocytes of fatigued rat bone using immunocytochemical staining and compared with TUNEL staining patterns. Bax and Bcl-2 were evident in osteocytes by 6 h after loading. Moreover, Bax and Bcl-2 in osteocytes were expressed differently as a function of distance from microdamage sites. The peak of Bax expression and TUNEL+ staining in osteocytes was observed immediately at the microcrack locus, which is where bone resorption occurs in this system; in contrast, Bcl-2 expression, the antiapoptotic signal, reached its greatest level at some distance (1-2 mm) from microcracks. These data suggest that near sites of microinjury in bone, those osteocytes that do not undergo apoptosis are prevented from doing so by active protection mechanisms. Moreover, the zone of apoptotic osteocytes around microcracks was effectively “walled in” by a surrounding halo of surviving osteocytes actively expressing Bcl-2. Thus, the expression pattern of apoptosis-inhibiting gene products by osteocytes surrounding the apoptotic osteocyte at microdamage sites also may provide important signals in the guidance of resorption processes that occur in association with osteocyte apoptosis after fatigue.

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