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Type: Journal article
Title: The role of osteocyte apoptosis in cancer chemotherapy-induced bone loss
Author: Shandala, T.
Ng, Y.
Hopwood, B.
Yip, Y.
Foster, B.
Xian, C.
Citation: Journal of Cellular Physiology, 2012; 227(7):2889-2897
Publisher: Wiley-Liss
Issue Date: 2012
ISSN: 0021-9541
Statement of
Tetyana Shandala, Yeap Shen Ng, Blair Hopwood, Yuen-Ching Yip, Bruce K. Foster and Cory J. Xian
Abstract: Intensive cancer chemotherapy leads to significant bone loss, the underlying mechanism of which remains unclear. The objective of this study was to elucidate mechanisms for effect of the commonly used anti-metabolite methotrexate (MTX) on osteocytes and on general bone homeostasis. The current study in juvenile rats showed that MTX chemotherapy caused a 4.3-fold increase in the number of apoptotic osteocytes in tibial metaphysis, which was accompanied by a 1.8-fold increase in the number of tartrate-resistant acid phosphatase-positive bone resorbing osteoclasts, and a 35% loss of trabecular bone. This was associated with an increase in transcription of the osteoclastogenic cytokines IL-6 (10-fold) and IL-11 (2-fold). Moreover, the metaphyseal bone of MTX-treated animals exhibited a 37.6% increase in the total number of osteocytes, along with 4.9-fold higher expression of the DMP-1 transcript. In cultured osteocyte-like MLO-Y4 cells, MTX treatment significantly increased caspase-3-mediated apoptosis, which was accompanied by the formation of plasma membrane-born apoptotic bodies and an increase in IL-6 (24-fold) and IL-11 (29-fold) mRNA expression. Conditioned media derived from MTX-treated MLO-Y4 cells was twice as strong as untreated media in its capacity to induce osteoclast formation in primary bone marrow osteoclast precursors. Thus, our in vivo and in vitro data suggested that MTX-induced apoptosis of osteocytes caused higher recruitment of DMP-1 positive osteocytes and increased osteoclast formation, which could contribute towards the loss of bone homeostasis in vivo.
Keywords: Osteoclasts
Rats, Sprague-Dawley
Bone Resorption
Acid Phosphatase
Extracellular Matrix Proteins
RNA, Messenger
Antimetabolites, Antineoplastic
Culture Media, Conditioned
Cell Differentiation
Caspase 3
Tartrate-Resistant Acid Phosphatase
Rights: Copyright © 2011 Wiley Periodicals, Inc.
DOI: 10.1002/jcp.23034
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Appears in Collections:Aurora harvest
Orthopaedics and Trauma publications

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