Inhibition of Oral Mucosal Cell Wound Healing by Bisphosphonates
Purpose
Bisphosphonates (BPs) are a widely used class of drugs that are effective in the treatment and prevention of osteoporosis, hypercalcemia of malignancy, and bone metastases associated with multiple myeloma, breast cancer, and other solid tumors. In the past several years there have been numerous reports describing the occurrence of osteonecrosis of the jaws (ONJ) associated with these drugs. Whether the ONJ lesion initiates in the oral mucosa or derives from the underlying bone is not well understood. In this report we describe the effect of pamidronate, a second-generation BP, on oral muscosal cells.
Materials and Methods
Murine oral keratinocytes were isolated and exposed to pamidronate at a range of clinically relevant doses. Cellular proliferation was measured using a MTS/PMS reagent-based kit and wound healing was examined with a scratch assay. To determine whether oral keratinocytes undergo apoptosis following exposure to pamidronate, TUNEL, caspase-3, and DAPI apoptosis assays were performed.
Results
We show that BP pretreatment of oral mucosal cells inhibits proliferation and wound healing at clinically relevant doses, and that this inhibition is not due to cellular apoptosis.
Conclusions
To our knowledge this is the first report investigating the effect of nitrogen-containing BPs on oral mucosal cells. This study suggests that BPs inhibit oral keratinocyte wound healing which may play a significant role in the initiation of ONJ.
⁎Associate Professor, Columbia University, College of Dental Medicine, Division of Oral and Maxillofacial Surgery, New York, NY.
†Technician, Columbia University, College of Dental Medicine, Division of Oral and Maxillofacial Surgery, New York, NY.
‡Associate Research Scientist, Columbia University, College of Physicians and Surgeons, Department of Medicine, Division of Endocrinology, New York, NY.
§Assistant Professor, Columbia University, College of Dental Medicine, Division of Oral and Maxillofacial Pathology, New York, NY.
¶Assistant Professor, Columbia University, College of Physicians and Surgeons, Department of Medicine, Division of Endocrinology, New York, NY.
⁎⁎Associate Professor, School of Medicine and Biomedical Sciences, Department of Biochemistry, State University of New York at Buffalo, Buffalo, NY.
††Assistant Professor, School of Medicine and Biomedical Sciences, Department of Biochemistry, State University of New York at Buffalo, Buffalo, NY.
‡‡Assistant Professor, Columbia University, College of Dental Medicine, Division of Oral and Maxillofacial Surgery, College of Physicians and Surgeons, Department of Dermatology, New York, NY.
Address correspondence and reprint requests to Dr Landesberg: Columbia University, College of Dental Medicine, Division of Oral and Maxillofacial Surgery, 630 W 168th Street, Box 20, New York, NY 10032
The project described was supported by Grant Number NIH 1 UL1 RR024156 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH) and NIH Roadmap for Medical Research, and its contents are solely the responsibility of the authors and do not necessary represent the official view of NCRR or NIH. Information on NCRR is available at http://www.ncrr.nih.gov/. Information on Reengineering the Clinical Research Enterprise can be obtained from http://nihroadmap.nih.gov/clinicalresearch/overview-translational.asp.
ABSTRACT