Visit our Expo - Redox and Inflammation signaling 2012

Session X : Cell death in cancer Poster X, 81
Induction of osteoclasts apoptosis by using a decoy oligodeoxynucleotide in vivo
mimicking a region of distal promoter C of ER alpha gene
Letizia Penolazzi, Margherita Zennaro, Ercolina Bianchini, Eros Magri, Elisabetta
Lambertini, Elisa Tavanti, Roberto Gambari and Roberta Piva.
Department of Biochemistry and Molecular Biology, University of Ferrara, Italy. Email:
piv@unife.it
The function of osteoclasts (OCs), the multinucleated cells responsible for the resorption of
extracellular bone matrix, are regulated by different kinds of hormones, cytokines,
inflammatory and transcription factors. Of particular interest is the role of estrogen receptor
alpha (ER) protein that mediates the action of estrogen. In particular, it suppresses OCs
formation and activity and inhibits OCs-mediated bone resorption in part by stimulating OCs
to undergo apoptosis through a receptor-mediated genomic action. In order to study
therapeutic strategies to control bone formation, we investigated the possibility to inhibit
osteoclastogenesis through a specific decoy strategy. We obtained an increase of ER
expression by interfering with the activity of a negative transcription factor and by removing
it with a decoy oligonucleotide (RA4-3’) mimicking a region of distal promoter C of ER gene.
We demonstrated that this decoy was able to induce apoptosis in human primary OCs, but not
in osteoblasts, in an estrogen dependent manner, increasing also Caspase 3 and Fas receptor
levels. These findings may be of relevance for a possible therapeutical approach for tumors,
bone metastasis and osteopenic diseases. At this purpose,the clinical orthodontic offers a good
opportunity to study in vivo the efficacy of our approach. In fact, the increased number and
activity of OCs is involved in the regulation of alveolar bone resorption during orthodontic
tooth movement, and also in the origin of dental problems in diseases of OCs activation
affecting the maxillo-mandibular bone. We designed in vivo experiments aimed at regulating
alveolar bone resorption. Six Wistar male rats were subjected to orthodontic forces, in
combination or not with RA4-3’ decoy treatment by using a split-mouth design. Examination
of paraffin sections of the excised molars showed that orthodontic forces caused a percentage
of apoptotic OCs that appears to be highly potentiated by RA4-3’, but not by scramble ODN.
These data confirm the results obtained in vitro with human OCs from peripheral blood,
suggesting an important correlation between ER and the possibility to modulate OCs
functions.
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