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Zoledronic acid and geranylgeraniol regulate cellular behaviour and angiogenic gene expression in human gingival fibroblasts
Author(s) -
Zafar S.,
Coates D. E.,
Cullinan M. P.,
Drummond B. K.,
Milne T.,
Seymour G. J.
Publication year - 2014
Publication title -
journal of oral pathology and medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.887
H-Index - 83
eISSN - 1600-0714
pISSN - 0904-2512
DOI - 10.1111/jop.12181
Subject(s) - geranylgeraniol , zoledronic acid , viability assay , mevalonate pathway , bisphosphonate , chemistry , biology , microbiology and biotechnology , cancer research , apoptosis , biochemistry , medicine , endocrinology , gene , farnesol , osteoporosis , biosynthesis
The mevalonate pathway ( MVP ) and the anti‐angiogenic effect of bisphosphonates have been shown to play a role in the pathogenesis of bisphosphonate‐related osteonecrosis of the jaw ( BRONJ ). This study determined the effect of the bisphosphonate, zoledronic acid and the replenishment of the MVP by geranylgeraniol on human gingival fibroblasts. Cell viability, apoptosis, morphological analysis using transmission electron microscopy, and gene expression for vascular endothelial growth factor A, bone morphogenic protein 2, ras homologue gene family member B, epiregulin and interferon‐alpha were conducted. Results showed cellular viability was decreased in the presence of zoledronic acid and the co‐addition of zoledronic acid with geranylgeraniol restored cell viability to control levels. Caspase 3/7 was detected in zoledronic‐acid‐treated cells indicating apoptosis. Transmission electron microscopy revealed dilation of the rough endoplasmic reticulum with zoledronic acid and the appearance of multiple lipid‐like vesicles following the addition of geranylgeraniol. Zoledronic acid significantly ( P < 0.05, FR > ±2) up‐regulated vascular endothelial growth factor A, bone morphogenic protein 2, ras homologue gene family member B and epiregulin at one or more time points but not interferon‐alpha. Addition of geranylgeraniol resulted in a reduction in the expression of all five genes compared with zoledronic‐acid‐treated human gingival fibroblasts. The study concluded geranylgeraniol partially reversed the effects of zoledronic acid in human gingival fibroblasts both at the cellular and genetic levels, suggesting the regulation of these genes is mediated via the mevalonate pathway.