Chronic ethanol exposure inhibits distraction osteogenesis in a mouse model: role of the TNF signaling axis.
Tumor necrosis factor-alpha (TNF-alpha) is an inflammatory cytokine that modulates osteoblastogenesis. In addition, the demonstrated inhibitory effects of chronic ethanol exposure on direct bone formation in rats are hypothetically mediated by TNF-alpha signaling. The effects in mice are unreported. Therefore, we hypothesized that in mice (1) administration of a soluble TNF receptor 1 derivative (sTNF-R1) would protect direct bone formation during chronic ethanol exposure, and (2) administration of recombinant mouse TNF-alpha (rmTNF-alpha) to ethanol naïve mice would inhibit direct bone formation. We utilized a unique model of limb lengthening (distraction osteogenesis, DO) combined with liquid diets to measure chronic ethanol's effects on direct bone formation. Chronic ethanol exposure resulted in increased marrow TNF, IL-1, and CYP 2E1 RNA levels in ethanol-treated vs. control mice, while no significant weight differences were noted. Systemic administration of sTNF-R1 during DO (8.0 mg/kg/2 days) to chronic ethanol-exposed mice resulted in enhanced direct bone formation as measured radiologically and histologically. Systemic rmTNF-alpha (10 microg/kg/day) administration decreased direct bone formation measures, while no significant weight differences were noted. We conclude that chronic ethanol-associated inhibition of direct bone formation is mediated to a significant extent by the TNF signaling axis in a mouse model.
Wahl
Elizabeth C
EC
Laboratory for Limb Regeneration Research, Arkansas Children's Hospital Research Institute, Little Rock, AR 72202, USA.
Aronson
James
J
Liu
Lichu
L
Liu
Zhendong
Z
Perrien
Daniel S
DS
Skinner
Robert A
RA
Badger
Thomas M
TM
Ronis
Martin J J
MJ
Lumpkin
Charles K
CK
D000818:Animals; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism; D002492:Central Nervous System Depressants / Q000008:administration & dosage / Q000494:pharmacology; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics / Q000378:metabolism; D000431:Ethanol / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D010012:Osteogenesis / Q000187:drug effects / Q000502:physiology; D019857:Osteogenesis, Distraction / Q000379:methods*; D010027:Osteotomy / Q000379:methods; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000037:antagonists & inhibitors; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D015398:Signal Transduction; D047990:TNF Receptor-Associated Factor 1 / Q000378:metabolism / Q000494:pharmacology; D013977:Tibia / Q000601:surgery; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000494:pharmacology*
D002492:Central Nervous System Depressants; D015850:Interleukin-6; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; D047990:TNF Receptor-Associated Factor 1; D014409:Tumor Necrosis Factor-alpha; D000431:Ethanol; D019392:Cytochrome P-450 CYP2E1