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

Narrative 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 #
1R01AR060055-01A1
Application #
8257292
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
2011-09-23
Budget End
2012-08-31
Support Year
1
Fiscal Year
2011
Total Cost
$372,600
Indirect Cost
Name
University of Pennsylvania
Department
Dentistry
Type
Schools of Dentistry
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Alharbi, Mohammed A; Zhang, Citong; Lu, Chanyi et al. (2018) FOXO1 Deletion Reverses the Effect of Diabetic-Induced Impaired Fracture Healing. Diabetes 67:2682-2694
Zhang, Citong; Feinberg, Daniel; Alharbi, Mohammed et al. (2018) Chondrocytes Promote Vascularization in Fracture Healing Through a FOXO1-Dependent Mechanism. J Bone Miner Res :
Graves, Dana T; Alshabab, Ahmed; Albiero, Mayra Laino et al. (2018) Osteocytes play an important role in experimental periodontitis in healthy and diabetic mice through expression of RANKL. J Clin Periodontol 45:285-292
Lim, Jason C; Ko, Kang I; Mattos, Marcelo et al. (2017) TNF? contributes to diabetes impaired angiogenesis in fracture healing. Bone 99:26-38
Zhang, Chenying; Lim, Jason; Liu, Jian et al. (2017) FOXO1 expression in keratinocytes promotes connective tissue healing. Sci Rep 7:42834
Tarapore, Rohinton S; Lim, Jason; Tian, Chen et al. (2016) NF-?B Has a Direct Role in Inhibiting Bmp- and Wnt-Induced Matrix Protein Expression. J Bone Miner Res 31:52-64
Yu, Weiling; Bien-Aime, Stephan; Mattos, Marcelo et al. (2016) Sustained, localized salicylic acid delivery enhances diabetic bone regeneration via prolonged mitigation of inflammation. J Biomed Mater Res A 104:2595-603
Wang, Yu; Dong, Guangyu; Jeon, Hyeran Helen et al. (2015) FOXO1 mediates RANKL-induced osteoclast formation and activity. J Immunol 194:2878-87
Ko, Kang I; Coimbra, Leila S; Tian, Chen et al. (2015) Diabetes reduces mesenchymal stem cells in fracture healing through a TNF?-mediated mechanism. Diabetologia 58:633-642
Pacios, Sandra; Xiao, Wenmei; Mattos, Marcelo et al. (2015) Osteoblast Lineage Cells Play an Essential Role in Periodontal Bone Loss Through Activation of Nuclear Factor-Kappa B. Sci Rep 5:16694

Showing the most recent 10 out of 25 publications