Although matrix metalloproteinases (MMPs) have been implicated in periodontitis, their role in altering the equilibrium between bone synthesis and degradation during periodontal breakdown has not been investigated. One component that may contribute to the induction of MMPs in periodontal disease is fibronectin (FN) fragments. FN fragments are found in chronic periodontitis and induce MMPs in periodontal ligament (PDL) cells. The mechanism by which MMPs cause bone breakdown in response to FN fragments may include their direct degradation of the collagenous matrix thereby facilitating osteoclastic bone resorption. Our preliminary data demonstrate that several FN fragments enhance osteoclastic activity that is paralleled by increases in MMP-9 and MMP-1, and inhibited by a MMP inhibitor. Additionally, we have shown that an increase in collagenolytic activity including that triggered by FN fragments attributable to MMP-1 and possibly MMP-13 is strongly correlated with the inhibition of osteoblastic phenotype in PDL cells. These data suggest that FN fragments may perpetuate periodontal disease by increasing net bone loss through induction of specific MMPs, which lead to disturbances in the osteogenic:osteolytic equilibrium. The overlying hypothesis of these studies is that specific MMPs induced by periodontal disease-associated FN fragments potentiate the disease by enhancing osteoclast activity and diminishing osteoblast differentiation. This investigation will assess the contribution of the FN fragment-MMP-osteoclast/osteoblast axis to periodontal breakdown by 1) determining the contribution of specific MMPs to osteoclastic bone resorption, 2) identifying the role of collagenolytic MMPs in inhibiting osteoblastic differentiation of PDL cells, and 3) determining the contribution of these FN fragment-induced MMPs in both cells to osteoclastic resorption and inhibition of osteoblastic differentiation of PDL cells in co-culture systems. These studies will provide a fundamental understanding of the basis for bone loss in periodontal disease and other osteolytic diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE016671-02
Application #
7045964
Study Section
Oral, Dental and Craniofacial Sciences Study Section (ODCS)
Program Officer
Lumelsky, Nadya L
Project Start
2005-04-01
Project End
2010-03-31
Budget Start
2006-04-01
Budget End
2007-03-31
Support Year
2
Fiscal Year
2006
Total Cost
$351,597
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Dentistry
Type
Schools of Dentistry
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109