Novel therapy to reverse the cellular effects of bisphosphonates on primary human oral fibroblasts.

Abstract

PURPOSE:

Osteonecrosis of the jaws (ONJ) is a clinical condition that is characterized by a nonhealing breach in the oral mucosa resulting in exposure of bone and has been increasingly reported in patients receiving bisphosphonate (BP) therapy. Although the pathogenesis and natural history of ONJ remain ill-defined, it appears that the oral soft tissues play a critical role in the development of this condition. We examined the effects of the nitrogen-containing BPs pamidronate and zoledronate on primary human gingival fibroblasts.

MATERIALS AND METHODS:

Primary gingival fibroblasts were exposed to clinically relevant doses of pamidronate and zoledronate. Cellular proliferation was measured with an MTS/PMS reagent-based kit (Promega, Madison, WI), scratch wound assays were performed to measure cellular migration, and apoptosis was measured by use of terminal deoxynucleotidyl transferase-mediated dUTP-FITC end labeling and caspase assays. The BP-exposed cells were treated with 10-ng/mL recombinant human platelet-derived growth factor BB (rhPDGF-BB) and 50-μmol/L geranylgeraniol (GGOH).

RESULTS:

Gingival fibroblasts are significantly more sensitive to inhibition of proliferation by zoledronate compared with pamidronate. Exposure of these cells to pamidronate but not zoledronate resulted in an increase in cellular apoptosis. Furthermore, exposure of gingival fibroblasts to pamidronate or zoledronate resulted in a decrease in cellular migration. We show that these defects are due to a loss of cell-substratum adhesion and a reduction of F-actin bundles. Finally, we show that the addition of rhPDGF-BB and GGOH in vitro is able to partially rescue the cell proliferation, migration, and adhesion defects.

CONCLUSION:

The cytotoxic effects of BPs on oral fibroblasts and their significant reversal by the addition of GGOH and rhPDGF-BB provide both the potential mechanism and treatment options for ONJ.

• Authors: Matthew Cozin, Bradley M Pinker, Kimberley Solemani, Jeremy M Zuniga, Stephen C Dadaian, Serge Cremers, Regina Landesberg, Srikala Raghavan
• Journal: Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons (J Oral Maxillofac Surg) Vol. 69 Issue 10 Pg. 2564-78 (Oct 2011) ISSN: 1531-5053 [Electronic] United States
• PMID: 21807448 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.

Chemical References

• Actins
• Bone Density Conservation Agents
• Diphosphonates
• Diterpenes
• Imidazoles
• Platelet-Derived Growth Factor
• Proto-Oncogene Proteins c-sis
• Recombinant Proteins
• Becaplermin
• Zoledronic Acid
• geranylgeraniol
• Caspase 3
• Pamidronate

Topics

• Actins (metabolism)
• Apoptosis
• Becaplermin
• Bone Density Conservation Agents (adverse effects)
• Caspase 3 (metabolism)
• Cell Adhesion (drug effects)
• Cell Culture Techniques
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Diphosphonates (adverse effects)
• Diterpenes (pharmacology)
• Fibroblasts (drug effects)
• Gingiva (cytology, drug effects)
• Humans
• Imidazoles (adverse effects)
• In Situ Nick-End Labeling
• Pamidronate
• Platelet-Derived Growth Factor (pharmacology)
• Proto-Oncogene Proteins c-sis
• Recombinant Proteins (pharmacology)
• Wound Healing (drug effects)
• Zoledronic Acid