“These results suggest that diabetes-enhanced TNF-alpha increases the expression of resorptive factors in chondrocytes through a process that involves activation of FOXO1, and that TNF-alpha dysregulation leads to enhanced osteoclast formation and accelerated loss of cartilage.”—Dana T. Graves, DDS
According to the study, high levels of TNF-α activate transcription factor Forkhead Box 01 (FOXO1), which has been shown to be elevated in chondrocytes of diabetic fracture calluses in a TNF dependent manner, the researchers report.Inflammation genes turned on in diabetes
Using a model of multiple low-dose streptozotocin-induced diabetes, the researchers showed an up-regulation of gene sets related to inflammation, including TNF signaling in the diabetic group, during a period in fracture healing when cartilage is being replaced by bone. This change coincided with elevated osteoclast numbers and accelerated removal of cartilage in the diabetic group, which was reflected by smaller callus size.
“These results suggest that diabetes-enhanced TNF-alpha increases the expression of resorptive factors in chondrocytes through a process that involves activation of FOXO1 and that TNF-alpha dysregulation leads to enhanced osteoclast formation and accelerated loss of cartilage,” concluded Dana T. Graves, DDS, a professor of periodontics at the University of Medicine and Dentistry in Newark, NJ and Thomas Einhorn, MD, and Louis Gerstenfeld, MD, of Boston University Medical Center.
Going forward, the group plans to "examine the effect of FOXO1 on mineralized tissue to examine how it may regulate factors that control bone resorption and osteoclastogenesis, in addition to effects it may have on osteoblastic cells."
Translating research into practice: general TNF blockade won't work
General TNF blockade is not likely to be a safe strategy for improving fracture healing in diabetics, however.
“TNF blockade also effects the antibacterial host defense and it probably would not be practical,” said Dr. Graves. “However, there may be other ways to treat the enhanced inflammation and loss of callus in diabetic fracture healing.”
Go after the FOXO1
“Diabetes can affect fracture healing from 2 standpoints—catabolic and anabolic. The field has focused on the anabolic aspect, but it may also be useful to consider the catabolic aspect,” Dr. Graves said.
Most diabetic complications have an inflammatory component.
“If you specifically look at diabetic complications, inflammation is a common characteristic. Elevation of TNF and FOXO1 are also common characteristics of several different diabetic complications including diabetic retinopathy and impaired soft tissue wound healing,” Dr. Graves said. “Cytokines and transcription factors such as FOXO1 are upregulated in tissues affected by diabetes, and blocking them in animal models seems to improve deficits caused by diabetes.”
Reference
1. Alblowi J, Kayal RA, Siquera M, et al.. High Levels of TNF-α Contribute to Accelerated Loss of Cartilage in Diabetic Fracture Healing. The American Journal of Pathology. 2009;175:1574-1585.