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24 January 2019 : Laboratory Research  

Epidermal Growth Factor Reverses the Inhibitory Effects of the Bisphosphonate, Zoledronic Acid, on Human Oral Keratinocytes and Human Vascular Endothelial Cells In Vitro via the Epidermal Growth Factor Receptor (EGFR)/Akt/Phosphoinositide 3-Kinase (PI3K) Signaling Pathway

Qizhang Wang1ABCDEF, Jiyuan Liu1ADFG, Ting Guo1BCD, Dazhong Liu2FG, Jian Pan1AG*

DOI: 10.12659/MSM.911579

Med Sci Monit 2019; 25:700-710


BACKGROUND: Medication-related osteonecrosis of the jaw (MRONJ) is due to the direct effects of drug toxicity and the effects on angiogenesis. The aims of this study were to evaluate the effects of treatment with the bisphosphonate, zoledronic acid, on human oral keratinocytes (HOKs) and human umbilical vein endothelial cells (HUVECs) in vitro, and whether epidermal growth factor (EGF) could alter these effects.

MATERIAL AND METHODS: HOKs and HUVECs were incubated with zoledronic acid or EGF. Cell viability was assessed by the cell counting kit-8 (CCK-8), cell apoptosis was studied using Annexin-V conjugated to fluorescein isothiocyanate (FITC). Angiogenesis was studied by observing HUVEC tube formation and cell migrations using a transwell assay. A scratch wound assay investigated cell migration of HOKs. Western blot measured expression levels of phosphorylated epidermal growth factor receptor (EGFR), Akt, phosphoinositide 3-kinase (PI3K), the mechanistic target of rapamycin (mTOR), and endothelial nitric oxide synthase (eNOS).

RESULTS: Zoledronic acid treatment (5 µmol/L) significantly inhibited cell viability and cell migration of HOKs and HUVECs and angiogenesis of HUVECS (P<0.05); EGF partially reversed these effects (P<0.05). Zoledronic acid treatment of HOKs and HUVECs had no significant effects on apoptosis (P>0.05), but significantly reduced expression levels of p-EGFR, p-Akt, p-PI3K, p-mTOR), and p-eNOS (P<0.05); EGF partially reversed these effects and increased the expression levels (P<0.05).

CONCLUSIONS: EGF partially reversed the effects of the bisphosphonate, zoledronic acid, on HOKs and HUVECs in vitro via the EGFR/Akt/PI3K signaling pathway. Further studies are required to determine the effects of EGF on MRONJ including bisphosphonate-related osteonecrosis of the jaw.

Keywords: Bisphosphonate-Associated Osteonecrosis of the Jaw, endothelial cells, Epidermal Growth Factor, Keratinocytes, Proto-Oncogene Proteins c-akt, Receptor, Epidermal Growth Factor, ErbB receptors, Human Umbilical Vein Endothelial Cells, Neovascularization, Pathologic, Neovascularization, Physiologic, Nitric Oxide Synthase Type III, Phosphatidylinositol 3-Kinases, zoledronic acid

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Medical Science Monitor eISSN: 1643-3750
Medical Science Monitor eISSN: 1643-3750