Effect of zoledronic acid on oral fibroblasts and epithelial cells: a potential mechanism of bisphosphonate-associated osteonecrosis.
Article Details
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Scheper MA, Badros A, Chaisuparat R, Cullen KJ, Meiller TF
Effect of zoledronic acid on oral fibroblasts and epithelial cells: a potential mechanism of bisphosphonate-associated osteonecrosis.
Br J Haematol. 2009 Mar;144(5):667-76. doi: 10.1111/j.1365-2141.2008.07504.x. Epub 2008 Nov 20.
- PubMed ID
- 19036117 [ View in PubMed]
- Abstract
Osteonecrosis of the jaw secondary to bisphosphonate infusion (zoledronic acid-ZA) is assumed to be a bone disease. This study investigated the effects of ZA on soft tissues using oral mucosal cells as an in vitro model of soft tissue cell death in the pathogenesis of bone necrosis. Human gingival fibroblast and keratinocyte cell lines were exposed to different concentrations of ZA (0.25-3 micromol/l), using 1 micromol/l as the expected baseline concentration. A dose-response effect on apoptosis and cell proliferation [Terminal deoxynucleotidyl transferase-mediated dUTP-Biotin End Labelling and Annexin V or Coulter counter and 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetr azolium), respectively] was observed with increasing ZA concentrations; both reversed using siRNA against caspase 3 or 9. Gene expression analysis using RT(2) Profiler polymerase chain reaction Arrays demonstrated the differential expression of multiple genes involved in apoptosis including those that encode TNF, BCL-2, Caspase, IAP, TRAF and Death Domain families. Western blot analysis confirmed the presence of activated forms of caspase 3 and 9 and underexpression of survivin protein expression. This study demonstrated that low concentrations of ZA rapidly and directly affected the oral mucosal tissues though the induction of a gene-regulated apoptotic process. These findings support the potential for soft tissue injury as an initiating/potentiating event for osteonecrosis.
DrugBank Data that Cites this Article
- Pharmaco-transcriptomics
Drug Drug Groups Gene Gene ID Change Interaction Chromosome Zoledronic acid Approved BAD 572 upregulated zoledronic acid results in increased expression of BAD mRNA 11q13.1 Zoledronic acid Approved BAG1 573 upregulated zoledronic acid results in increased expression of BAG1 mRNA 9p13.3 Zoledronic acid Approved BAG3 9531 upregulated zoledronic acid results in increased expression of BAG3 mRNA 10q26.11 Zoledronic acid Approved BAX 581 downregulated zoledronic acid results in decreased expression of BAX mRNA 19q13.33 Zoledronic acid Approved BCL2A1 597 downregulated zoledronic acid results in decreased expression of BCL2A1 mRNA 15q25.1 Zoledronic acid Approved BCL2L1 598 upregulated zoledronic acid results in increased expression of BCL2L1 mRNA 20q11.21 Zoledronic acid Approved BCL2L2 599 upregulated zoledronic acid results in increased expression of BCL2L2 mRNA 14q11.2 Zoledronic acid Approved BID 637 upregulated zoledronic acid results in increased expression of BID mRNA 22q11.21 Zoledronic acid Approved BIRC2 329 downregulated zoledronic acid results in decreased expression of BIRC2 mRNA 11q22.2 Zoledronic acid Approved BIRC6 57448 downregulated zoledronic acid results in decreased expression of BIRC6 mRNA 2p22.3 Zoledronic acid Approved BIRC8 112401 downregulated zoledronic acid results in decreased expression of BIRC8 mRNA 19q13.42 Zoledronic acid Approved BNIP3 664 downregulated zoledronic acid results in decreased expression of BNIP3 mRNA 10q26.3 Zoledronic acid Approved CASP14 23581 downregulated zoledronic acid results in decreased expression of CASP14 mRNA 19p13.12 Zoledronic acid Approved CASP8 841 upregulated zoledronic acid results in increased expression of CASP8 mRNA 2q33.1 Zoledronic acid Approved CD40LG 959 downregulated zoledronic acid results in decreased expression of CD40LG mRNA Xq26.3 Zoledronic acid Approved DAPK1 1612 downregulated zoledronic acid results in decreased expression of DAPK1 mRNA 9q21.33 Zoledronic acid Approved FAS 355 upregulated zoledronic acid results in increased expression of FAS mRNA 10q23.31 Zoledronic acid Approved LTBR 4055 upregulated zoledronic acid results in increased expression of LTBR mRNA 12p13 Zoledronic acid Approved TNF 7124 upregulated zoledronic acid results in increased expression of TNF mRNA 6p21.33 Zoledronic acid Approved TNFRSF10A 8797 upregulated zoledronic acid results in increased expression of TNFRSF10A mRNA 8p21.3 Zoledronic acid Approved TNFRSF11B 4982 upregulated zoledronic acid results in increased expression of TNFRSF11B mRNA 8q24.12 Zoledronic acid Approved TNFRSF1A 7132 upregulated zoledronic acid results in increased expression of TNFRSF1A mRNA 12p13.31 Zoledronic acid Approved TNFRSF21 27242 upregulated zoledronic acid results in increased expression of TNFRSF21 mRNA 6p12.3 Zoledronic acid Approved TNFRSF25 8718 downregulated zoledronic acid results in decreased expression of TNFRSF25 mRNA 1p36.31 Zoledronic acid Approved TNFRSF9 3604 downregulated zoledronic acid results in decreased expression of TNFRSF9 mRNA 1p36.23 Zoledronic acid Approved TRADD 8717 upregulated zoledronic acid results in increased expression of TRADD mRNA 16q22.1 Zoledronic acid Approved TRAF2 7186 upregulated zoledronic acid results in increased expression of TRAF2 mRNA 9q34.3 Zoledronic acid Approved TRAF3 7187 upregulated zoledronic acid results in increased expression of TRAF3 mRNA 14q32.32 Zoledronic acid Approved XIAP 331 downregulated zoledronic acid results in decreased expression of XIAP mRNA Xq25