Tumor necrosis factor-alpha mediates diabetes-enhanced apoptosis of matrix-producing cells and impairs diabetic healing.
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.
Liu
Rongkun
R
Department of Periodontology and Oral Biology, Boston University School of Dental Medicine, Boston, Massachusetts 02118, USA.
Bal
Harbinder S
HS
Desta
Tesfahun
T
Behl
Yugal
Y
Graves
Dana T
DT
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001861:Bone Regeneration; D053148:Caspase 3; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D000068800:Etanercept; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D007074:Immunoglobulin G / Q000494:pharmacology; D051379:Mice; D008817:Mice, Mutant Strains; D016966:Porphyromonas gingivalis; D018124:Receptors, Tumor Necrosis Factor; D012535:Scalp / Q000166:cytology / Q000382:microbiology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D014945:Wound Healing / Q000187:drug effects
D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D000068800:Etanercept