Diabetes causes osteopenia and increased fracture risk. Furthermore, diabetes interferes with fracture repair of the mandible and long bones. We have recently found that a major difference between normoglycemic and diabetic mice is the accelerated loss of cartilage in the diabetic group. This points to a previously unrecognized catabolic defect in diabetic fracture healing and suggests that rapid removal of cartilage may reduce the anlage for endochondral bone formation. Furthermore, diabetic fracture calluses are characterized by significantly elevated levels of FOXO1 activity and increased FOXO1 nuclear translocation in chondrocytes. The goal of the proposed studies is to test the hypothesis that diabetes enhanced FOXO1 activity alters gene expression in chondrocytes that contributes to impaired diabetic fracture healing.
Aim 1 will investigate mechanisms by which conditions that are present in diabetic fracture healing, elevated TNF-1, advanced glycation end products or high glucose levels stimulate FOXO1 activation in chondrogenic cells. These experiments will FOXO1 post- translational modification assesses by mass spectrometry which is significant since it regulates FOXO1 nuclear localization and DNA binding activity.
Aim 2 will establish whether chondrocyte specific deletion of FOXO1 using the Cre/lox system will reverse the impact of diabetes on the accelerated removal of cartilage. To investigate how FOXO1 could affect the healing process we will examine FOXO1 deletion on pro- osteoclastogenic gene expression, osteoclast numbers and mechanical strength.
Aim 3 will utilize the same mice to determine whether conditional deletion of FOXO1 in chondrocytes reverses diabetes enhanced chondrocyte apoptosis and pro-apoptotic gene expression during diabetic fracture healing.

Public Health Relevance

Diabetes causes osteopenia and increased fracture risk. Furthermore, diabetes interferes with fracture repair of the mandible and long bones. We have recently found that a major difference between normoglycemic and diabetic mice is the accelerated loss of cartilage in the diabetic group. This points to a previously unrecognized catabolic defect in diabetic fracture healing and suggests that rapid removal of cartilage may reduce the anlage for endochondral bone formation. Furthermore, diabetic fracture calluses are characterized by significantly elevated levels of the transcription factor FOXO1 and increased FOXO1 nuclear translocation in chondrocytes. The goal of the proposed studies is to test the hypothesis that diabetes alters pro-osteoclastogenic and pro- apoptotic gene expression in chondrocytes that contributes to impaired diabetic fracture healing through a mechanism mediated by enhanced activation of FOXO1.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR060055-02
Application #
8337402
Study Section
Special Emphasis Panel (ZRG1-MOSS-S (02))
Program Officer
Sharrock, William J
Project Start
2011-09-23
Project End
2016-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
2
Fiscal Year
2012
Total Cost
$359,100
Indirect Cost
$121,500
Name
University of Pennsylvania
Department
Dentistry
Type
Schools of Dentistry
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Wang, Yu; Zhou, Yanmin; Graves, Dana T (2014) FOXO transcription factors: their clinical significance and regulation. Biomed Res Int 2014:925350
Wada, Keisuke; Yu, Weiling; Elazizi, Mohamad et al. (2013) Locally delivered salicylic acid from a poly(anhydride-ester): impact on diabetic bone regeneration. J Control Release 171:33-7
Alblowi, Jazia; Tian, Chen; Siqueira, Michelle F et al. (2013) Chemokine expression is upregulated in chondrocytes in diabetic fracture healing. Bone 53:294-300
Ponugoti, Bhaskar; Dong, Guangyu; Graves, Dana T (2012) Role of forkhead transcription factors in diabetes-induced oxidative stress. Exp Diabetes Res 2012:939751