Ethanol-induced inhibition of bone formation in a rat model of distraction osteogenesis: a role for the tumor necrosis factor signaling axis.
BACKGROUND
Chronic ethanol exposure inhibits the rapid bone formation demonstrated during limb lengthening by distraction osteogenesis (DO). This inhibition is attenuated by simultaneous administration of antagonists to the cytokines interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha. The individual effects on inhibition of osteogenesis by these cytokines were tested. We hypothesized that administration of individual antagonists to these cytokines [IL-1 receptor antagonist (IL-1ra) or polyethylene glycol-conjugated soluble TNF receptor type 1 (sTNFR1)] would enhance DO and that the individual administration of each cytokine [recombinant rat (rr) IL-1 or recombinant rat (rr) TNF] would inhibit DO.


METHODS
Rats were either infused with a liquid diet with or without ethanol (antagonist studies) or given rat chow (recombinant studies) and underwent tibial fractures stabilized with external fixators for DO. The bioactive substances were administered by systemic (antagonist studies) or local (recombinant) diffusion.


RESULTS
A comparison of histologic sections from these distracted tibias demonstrated a protective effect on bone formation by sTNFR1 (p<0.05), unexpectedly, an IL-1ra-related decrease in bone formation (p<0.02), significant decreases in bone formation with rrTNF compared with the vehicle controls (p<0.02), and no significant changes in bone formation with rrIL-1. The cellular responses (fibroblastic and inflammatory cells) were unique for each recombinant cytokine administered.


CONCLUSIONS
These results suggest that the osteoinhibitory effects of chronic ethanol exposure are mediated in part by the TNF signaling axis.
Wahl
Elizabeth C
EC
Department of Pediatrics, College of Medicine, University of Arkansas for Medical Sciences, and Laboratory for Limb Regeneration Research, Arkansas Children's Hospital Research Institute, Little Rock, Arkansas 72202, USA.
Perrien
Daniel S
DS
Aronson
James
J
Liu
Zhendong
Z
Fletcher
Terry W
TW
Skinner
Robert A
RA
Feige
Ulrich
U
Suva
Larry J
LJ
Badger
Thomas M
TM
Lumpkin
Charles K
CK
D000437:Alcoholism / Q000503:physiopathology*; D000818:Animals; D001861:Bone Regeneration / Q000187:drug effects*; D000431:Ethanol / Q000633:toxicity*; D007375:Interleukin-1 / Q000502:physiology*; D008297:Male; D019857:Osteogenesis, Distraction; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D007375:Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D000431:Ethanol