Nitrogen-containing bisphosphonates (n-BP) effectively control dysregulated bone turnover, osteolytic lesions of cancer metastasis and have anti-tumor activities. Unfortunately, osteonecrosis of the jaw (ONJ) is a major complication of n-BP therapy. Reasons for jaw-specific location of n-BP related osteonecrosis are unclear making it challenging to design targeted therapies. n-BPs act on osteoclasts and cancer cells by blocking the farnesyl pyrophosphate (FPP) synthase in the mevalonate signaling pathway;the outcome is loss of prenylation of small GTPase signaling proteins and dysregulation of cell survival and differentiation. We have shown that orofacial bone marrow stromal cells or bone mesenchymal stem cells (BMSCs) from neural crest-derived maxilla/mandible (OFMSCs) are highly proliferative with long population doublings relative to those of mesoderm-derived iliac bone (ICMSCs) and long bones (LBMSCs). Therefore, they may readily succumb to n-BP similar to rapidly proliferative cancer cells. Our preliminary studies showed that OFMSCs are indeed more sensitive to n-BP than ICMSCs based on enhanced n-BP uptake, slow elimination from the cytosol, decreased survival and decreased osteogenic differentiation. We hypothesize that sensitivity of OFMSCs to n-BP contributes in part to initiation of ONJ based on site-dependent n-BP uptake, intracellular processing, inhibition of FPP synthase in the mevalonate pathway and consequent loss of prenylation of small GTPase signaling proteins.
In aim 1 we will determine how uptake and intracellular trafficking of n-BP in OFMSCs modulates survival and aim 2 will explore BMSC-based therapy to prevent ONJ in a small animal model. The goal is to formulate preventive measures for ONJ.

Public Health Relevance

Bisphosphonate is an effective therapy for bone complications associated with cancer metastasis but a major complication is jaw bone necrosis. We want to understand how jaw bone stem cells readily succumb to effects of bisphosphonate so the complication of jaw necrosis can be prevented.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21DE022826-02
Application #
8537887
Study Section
Special Emphasis Panel (ZRG1-MOSS-K (80))
Program Officer
Wan, Jason
Project Start
2012-09-01
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
2
Fiscal Year
2013
Total Cost
$192,000
Indirect Cost
$72,000
Name
University of Pennsylvania
Department
Dentistry
Type
Schools of Dentistry
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Akintoye, So (2014) Osteonecrosis of the jaw from bone anti-resorptives: impact of skeletal site-dependent mesenchymal stem cells. Oral Dis 20:221-2
Akintoye, Sunday O; Boyce, Alison M; Collins, Michael T (2013) Dental perspectives in fibrous dysplasia and McCune-Albright syndrome. Oral Surg Oral Med Oral Pathol Oral Radiol 116:e149-55