In vivo effects of zoledronic acid on oral mucosal epithelial cells.
OBJECTIVE
Osteonecrosis of the jaw is a serious complication of bisphosphonate treatment for which the pathophysiology is unknown. The purpose of this study was to investigate whether in vivo zoledronic acid (ZA) induces alterations in cell proliferation, apoptosis, and matrix metalloproteinases (MMPs) expression in oral mucosal epithelial cells.


METHODS
One-year-old dogs were either untreated (control group) or given high doses of intravenous ZA (ZA group) for 3 months. The doses of ZA were equivalent to those given to cancer patients, yet were administered two times more frequently (every 2 weeks). Mucosal tissues were assessed immunohistochemically for cell proliferation (proliferating cell nuclear antigen, PCNA), matrix metalloproteinase (MMP) expression, and apoptosis (caspase 3 and TUNEL).


RESULTS
There were no significant differences between the groups with respect to PCNA, MMP-2, MMP-14, and TUNEL positive cells. However, the expression of MMP-9 was significantly higher in the control group than in the ZA group (P < 0.05), whereas the expression of caspase 3 was significantly lower in the control group than in the ZA group (P < 0.05).


CONCLUSIONS
These results suggest that high doses of ZA resulted in higher levels of apoptosis and lower levels of MMP-9 in the oral epithelial cells supporting the idea of bisphosphonate treatment affects the oral mucosa.
Allam
E
E
Department of Oral Biology, Indiana University School of Dentistry, Indianapolis, IN, USA.
Allen
Mr
M
Chu
T-M
TM
Ghoneima
A
A
Jack Windsor
L
L
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D050071:Bone Density Conservation Agents / Q000008:administration & dosage / Q000494:pharmacology*; D053148:Caspase 3 / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004164:Diphosphonates / Q000008:administration & dosage / Q000494:pharmacology*; D004285:Dogs; D004847:Epithelial Cells / Q000187:drug effects; D005260:Female; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007275:Injections, Intravenous; D053511:Matrix Metalloproteinase 14 / Q000187:drug effects; D020778:Matrix Metalloproteinase 2 / Q000187:drug effects; D020780:Matrix Metalloproteinase 9 / Q000187:drug effects; D023421:Models, Animal; D009061:Mouth Mucosa / Q000166:cytology / Q000187:drug effects*; D018809:Proliferating Cell Nuclear Antigen / Q000187:drug effects; D000077211:Zoledronic Acid
D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D018809:Proliferating Cell Nuclear Antigen; D000077211:Zoledronic Acid; D053148:Caspase 3; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D053511:Matrix Metalloproteinase 14