The role of osteocyte apoptosis in cancer chemotherapy-induced bone loss

Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, Division of Health Sciences, University of South Australia, Adelaide, Australia.
Journal of Cellular Physiology (Impact Factor: 3.84). 07/2012; 227(7):2889-97. DOI: 10.1002/jcp.23034
Source: PubMed


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.

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    • "esorption . Apo - ptotic osteocytes release osteoclastogenesis - promoting factors , includ - ing soluble receptor activator of nuclear factor κ - B ligand ( sRankl ) , IL - 6 and soluble IL - 6 receptor ( sIL - 6R ) and induce TNF - α expression in osteoclast precursors in vitro expression and the conditioned media promote osteo - clastogenesis ( Shandala et al . 2012 ) . Further , apoptotic MLO - Y4 - conditioned media promote osteoclast precursor adhesion to endothelial cells via intercellular adhesion mole - cule 1 ( ICAM - 1 ) , probably through the induction of IL - 6 and soluble IL - 6 receptor ( Cheung et al . 2012 ) . Therefore , apoptotic osteocytes can upregulate the expression of osteoclas"
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