Int J Med Sci 2019; 16(12):1534-1540. doi:10.7150/ijms.36994

Research Paper

Impact of bisphosphonates on the proliferation and gene expression of human fibroblasts

Francisco Javier Manzano-Moreno1,2*, Rebeca Illescas-Montes2,3*, Lucia Melguizo-Rodriguez2,3, Victor J. Costela-Ruiz2,3, Olga García-Martínez2,3, Concepción Ruiz2,3,4✉, Javier Ramos-Torrecillas2,3✉

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

This is an open access article distributed under the terms of the Creative Commons Attribution License ( See for full terms and conditions.
Manzano-Moreno FJ, Illescas-Montes R, Melguizo-Rodriguez L, Costela-Ruiz VJ, García-Martínez O, Ruiz C, Ramos-Torrecillas J. Impact of bisphosphonates on the proliferation and gene expression of human fibroblasts. Int J Med Sci 2019; 16(12):1534-1540. doi:10.7150/ijms.36994. Available from

File import instruction


The aim of this study was to elucidate the role of fibroblasts in bisphosphonate-related osteonecrosis of the jaw (BRONJ), evaluating the effect of zoledronate, alendronate, and ibandronate on the proliferation of fibroblasts and on their expression of genes essential for fibroblast physiology. Human CCD-1064Sk epithelial fibroblast cells were incubated in culture medium with 10-5, 10-7, or 10-9 M zoledronate, alendronate, or ibandronate. The proliferative capacity of fibroblasts was determined by spectrophotometry (MTT) at 24 of culture. Real-time polymerase chain reaction (RT-PCR) was used to study the effects of BPs at a dose of 10-9 M on the expression of FGF, CTGF, TGF-β1, TGFβR1, TGFβR2, TGFβR3, DDR2, α-actin, fibronectin, decorin, and elastin. Fibroblasts proliferation was significantly increased at the lowest dose (10-9M) of each BP but was not affected at the higher doses (10-5 and 10-7M). The proliferation increase may be related to the rise in TGF-β1 and TGFβR1 expression detected after the treatment of cells with 10-9M of zoledronate, alendronate, or ibandronate. However, the expression of CTGF, DDR2, α-actin, fibronectin, and decorin decreased versus controls. The results of this in vitro study indicate that a very low BP dose (10-9 M) can significantly affect the physiology of fibroblasts, increasing their proliferative capacity and modulating the expression of multiple genes involved in their growth and differentiation.

Keywords: bisphosphonates, osteonecrosis, jaw, fibroblast, gene expression