Zoledronic acid and geranylgeraniol regulate cellular behaviour and angiogenic gene expression in human gingival fibroblasts.
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.
Faculty of Dentistry, Sir John Walsh Research Institute, University of Otago, Dunedin, New Zealand.
S
S
Zafar
D E
DE
Coates
M P
MP
Cullinan
B K
BK
Drummond
T
T
Milne
G J
GJ
Seymour
D000328:Adult; D017209:Apoptosis / Q000187:drug effects; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D055396:Bone Morphogenetic Protein 2 / Q000187:drug effects; D018929:Cell Culture Techniques; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004164:Diphosphonates / Q000494:pharmacology*; D004224:Diterpenes / Q000494:pharmacology*; D066260:Epiregulin / Q000032:analysis; D005204:Farnesol / Q000494:pharmacology; D005260:Female; D005347:Fibroblasts / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D005881:Gingiva / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D016898:Interferon-alpha / Q000187:drug effects; D008798:Mevalonic Acid / Q000378:metabolism; D046529:Microscopy, Electron, Transmission; D008875:Middle Aged; D018919:Neovascularization, Physiologic / Q000187:drug effects* / Q000235:genetics; D011106:Polyisoprenyl Phosphates / Q000378:metabolism; D012717:Sesquiterpenes / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects / Q000235:genetics; D000077211:Zoledronic Acid; D020743:rhoB GTP-Binding Protein / Q000187:drug effects
C525718:BMP2 protein, human; D050071:Bone Density Conservation Agents; D055396:Bone Morphogenetic Protein 2; D004164:Diphosphonates; D004224:Diterpenes; C587880:EREG protein, human; D066260:Epiregulin; D007093:Imidazoles; D016898:Interferon-alpha; D011106:Polyisoprenyl Phosphates; D012717:Sesquiterpenes; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D005204:Farnesol; D000077211:Zoledronic Acid; C004808:farnesyl pyrophosphate; C017338:geranylgeraniol; D020743:rhoB GTP-Binding Protein; C002963:geranylgeranyl pyrophosphate; D008798:Mevalonic Acid
Bisphosphonate-related osteonecrosis of the jaw; geranylgeraniol; human gingival fibroblasts; mevalonate pathway; zoledronic acid