International Journal of Medical Sciences

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25 May 2018

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Int J Med Sci 2018; 15(4):359-367. doi:10.7150/ijms.22627

Research Paper

Bisphosphonate Modulation of the Gene Expression of Different Markers Involved in Osteoblast Physiology: Possible Implications in Bisphosphonate-Related Osteonecrosis of the Jaw

Francisco Javier Manzano-Moreno1,2*, Javier Ramos-Torrecillas2,3*, Lucia Melguizo-Rodríguez2,3, Rebeca Illescas-Montes2,4, Concepción Ruiz2,3,5✉, Olga García-Martínez2,3

1. Biomedical Group (BIO277), Department of Stomatology, School of Dentistry, University of Granada, Spain.
2. Instituto Investigación Biosanitaria, ibs.Granada (Spain).
3. Biomedical Group (BIO277), Department of Nursing, Faculty of Health Sciences. University of Granada, Spain.
4. Biomedical Group (BIO277), Department of Nursing, Faculty of Nursing, Melilla. University of Granada, Spain.
5. Institute of Neuroscience, Parque Tecnológico Ciencias de la Salud, Armilla (Granada), University of Granada, Spain.
*Authors Francisco Javier Manzano-Moreno and Javier Ramos-Torrecillas contributed equally to this study.

Abstract

The aim of the present study was to elucidate the role of osteoblasts in bisphosphonates-related osteonecrosis of the jaw (BRONJ). The specific objective was to evaluate the effect on osteoblasts of two nitrogen-containing BPs (zoledronate and alendronate) and one non-nitrogen-containing BP (clodronate) by analyzing modulations in their expression of genes essential for osteoblast physiology. Real-time polymerase chain reaction (RT-PCR) was used to study the effects of zoledronate, alendronate, and clodronate at doses of 10-5, 10-7, or 10-9 M on the expression of Runx-2, OSX, ALP, OSC, OPG, RANKL, Col-I, BMP-2, BMP-7, TGF-β1, VEGF, TGF-βR1, TGF-βR2, and TGF-βR3 by primary human osteoblasts (HOBs) and MG-63 osteosarcoma cells. Expression of these markers was found to be dose-dependent, with no substantive differences between these cell lines. In general, results demonstrated a significant increase in TFG-β1, TGF-βR1, TGF-βR2, TGF-βR3, and VEGF expressions and a significant reduction in RUNX-2, Col-1, OSX, OSC, BMP-2, BMP-7, ALP, and RANKL expressions, while OPG expression varied according to the dose and cell line. The results of this in vitro study of HOBS and MG-63 cell lines indicate that low BP doses can significantly affect the expression of genes essential for osteoblast growth and differentiation and of genes involved in regulating osteoblast-osteoclast interaction, possibly by increasing TGF-β1 production. These findings suggest that osteoblasts may play an important role in BRONJ development, without ruling out other factors.

Keywords: bisphosphonates, osteoblast, BRONJ, gene expression, TGF-β1

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How to cite this article:
Manzano-Moreno FJ, Ramos-Torrecillas J, Melguizo-Rodríguez L, Illescas-Montes R, Ruiz C, García-Martínez O. Bisphosphonate Modulation of the Gene Expression of Different Markers Involved in Osteoblast Physiology: Possible Implications in Bisphosphonate-Related Osteonecrosis of the Jaw. Int J Med Sci 2018; 15(4):359-367. doi:10.7150/ijms.22627. Available from http://www.medsci.org/v15p0359.htm