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(American Journal of Pathology. 2006;168:757-764.)
© 2006 American Society for Investigative Pathology

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

From the Department of Periodontology and Oral Biology, Boston University School of Dental Medicine, Boston, Massachusetts

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 (TNF-) 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- 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- 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- treatment was within the range that is physiologically relevant. This enhanced healing may in part be explained by block-ing TNF--induced apoptosis of critical matrix-pro-ducing cells.

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