Tumor Necrosis Factor-α Mediates Diabetes-Enhanced Apoptosis of Matrix-Producing Cells and Impairs Diabetic Healing

Abstract

Diabetics suffer increased infection followed by increased apoptosis of fibroblasts and bone-lining cells during the healing process. To investigate a potential mechanism, we inoculated Porphyromonas gingivalis into the scalp of type 2 diabetic (db/db) or control mice and inhibited tumor necrosis factor alpha (TNF-alpha) with etanercept. Mice were euthanized at the early phase of infection (21 hours) or during the peak repair of the bacteria-induced wound (8 days). At 21 hours, TNF-alpha inhibition significantly reduced fibroblast apoptosis and caspase-3 activity in both diabetic and normoglycemic mice (P < 0.05). During healing etanercept reduced fibroblast apoptosis and caspase-3 activity by almost 50% in diabetic but not normoglycemic mice (P < 0.05). Concomitantly, etanercept significantly increased fibroblast number by 31% and new matrix formation by 72% in diabetic mice. When bone was examined during healing, administration of the TNF-alpha blocker reduced apoptosis of bone-lining cells by 53%, increased their number by 48%, and enhanced new bone formation by 140% in the diabetic group (P < 0.05). The degree of connective tissue and osseous healing stimulated in the diabetic mice by anti-TNF-alpha treatment was within the range that is physiologically relevant. This enhanced healing may in part be explained by block-ing TNF-alpha-induced apoptosis of critical matrix-producing cells.

Advanced glycation end products stimulate osteoblast apoptosis via the MAP kinase and cytosolic apoptotic pathways

“…Given the potential to shorten the lifespan of mature osteoblasts as well mesenchymal stem cells (25) AGE-stimulated apoptosis may represent an avenue through which osteogenesis is impaired in aged and diabetic individuals. However, AGEs do not represent the only mechanism for diabetes-enhanced osteoblast apoptosis as inhibition of TNF in vivo also reduces apoptosis of periosteal cells and promotes new bone formation (31). These and other reports underscore the potential importance of osteoblast apoptosis as a mechanism for impaired bone formation in diabetic and aged individuals (5,34,35).…”

TUNEL-positive cells in the surgical border of an amputation due to infected diabetic foot

“…Such plaques are considered vulnerable or high risk (33) due to their fragility and thrombogenic capacity, and they are characterized by a fibrous capsule, large number of macrophages and a nucleus rich in lipids, with an elevated content of proinflammatory factors (34). The infectious process in the IDP contributes to the development of apoptosis due to the action of lipopolysaccharide or proinflammatory cytokines such as tumor necrosis factor (35). Hyperglycemia increases the cytotoxic effect of LPS and ischemia (36).…”

Targeting activation-induced cytidine deaminase prevents colon cancer development despite persistent colonic inflammation

“…Inhibition of TNF-a and IL-12 suppressed AID expression with the decrease of colonic inflammation in IL-10 À/À mice To clarify the role of TNF-a and IL-12 in the pathophysiology of colonic inflammation in association with aberrant AID expression in the IL-10 À/À mice, the biologic activity of TNF-a and IL-12 was inhibited using the TNF antagonist etanercept and neutralizing IL-12p40 monoclonal antibody (mAb), respectively (Liu et al, 2006;Watanabe et al, 2006;Popivanova et al, 2008). First, we confirmed that the expression of both TNF-a and IL-12 was significantly upregulated in the cecum compared with the proximal and distal colon (Po0.05, Figure 2a).…”