The goal of the proposed studies is to test the hypothesis the diabetes negatively impacts periodontitis through a negative effect on osteoblasts/osteocytes. Preliminary Data establish that lineage specific down regulation of NF-?B activity in osteoblasts/osteocytes significantly reduces periodontitis. We have also shown that diabetes particularly affects osteoblastic cells and that diabetes causes uncoupling that contributes to periodontal bone loss. Our hypothesis is that diabetes impacts osteoblasts/osteocytes to promote periodontal bone loss through two distinct mechanisms. The first is that osteoblast/osteocyte-produced RANKL is significantly enhanced by diabetes and contributes to increased bone loss. The second is that diabetes suppresses bone formation in osteoblasts/osteocytes through NF-?B to reduce coupled bone formation thereby promoting more net bone loss. The latter is supported by new Preliminary Data that factors present in diabetes (high glucose levels, high levels of TNF and advanced glycation end products) stimulate NF-?B binding to bone matrix protein promoters. Moreover, NF-?B directly inhibits transcription of bone matrix proteins. This provides a novel mechanism for diabetes-suppressed expression of bone matrix proteins. We will definitively test the role of osteoblasts/osteocytes in diabetes-enhanced periodontitis by using lineage specific inhibition of NF-?B in transgenic (Col1?1.IKK-DN) mice and lineage specific deletion of RANKL in Col1?1.ERT2.Cre+.RANKL L/L mice and matched control mice. In summary, this competitive renewal will establish a mechanistic explanation for the observation that diabetes enhances the risk and severity of periodontal bone loss.

Public Health Relevance

The goal of the proposed studies is to test the hypothesis the diabetes negatively affects osteoblasts/osteocytes to aggravate periodontal bone loss. Our hypothesis is that diabetes-enhanced inflammation has a significant impact on osteoblasts/osteocytes to promote periodontal bone loss through two distinct mechanisms. The first is that diabetes increases osteoblast/osteocyte-produced RANKL through greater activation of NF-?B. The second is that diabetes impairs the ability of osteoblasts/osteocytes to limit coupled bone formation through an NF-?B mediated mechanism.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE017732-11
Application #
9600071
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Lumelsky, Nadya L
Project Start
2006-07-01
Project End
2020-11-30
Budget Start
2018-12-01
Budget End
2020-11-30
Support Year
11
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Dentistry
Type
Schools of Dentistry/Oral Hygn
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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