Direct bone formation during distraction osteogenesis does not require TNFα receptors and elevated serum TNFα fails to inhibit bone formation in TNFR1 deficient mice

Elizabeth C. Wahl, James Aronson, Lichu Liu, Robert A. Skinner, Mike J. Miller, Gael E. Cockrell, John L. Fowlkes, Kathryn M. Thrailkill, Robert C. Bunn, Martin J.J. Ronis, Charles K. Lumpkin

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

Distraction osteogenesis (DO) is a process which induces direct new bone formation as a result of mechanical distraction. Tumor necrosis factor-α (TNF) is a cytokine that can modulate osteoblastogenesis. The direct effects of TNF on direct bone formation in rodents are hypothetically mediated through TNF receptor 1 and/or 2 (TNFR1/2) signaling. We utilized a unique model of mouse DO to assess the effects of 1) TNFR homozygous null gene alterations on direct bone formation and 2) rmTNF on wild type (WT), TNFR1-/- (R1KO), and TNR2-/- (R2KO) mice. Radiological and histological analyses of direct bone formation in the distraction gaps demonstrated no significant differences between the WT, R1KO, R2KO, or TNFR1-/- and R2-/- (R1 and 2KO) mice. R1 and 2KO mice had elevated levels of serum TNF but demonstrated no inhibition of new bone formation. Systemic administration by osmotic pump of rmTNF during DO (10 μg/kg/day) resulted in significant inhibition of gap bone formation measures in WT and R2KO mice, but not in R1KO mice. We conclude that exogenous rmTNF and/or endogenous TNF act to inhibit new bone formation during DO by signaling primarily through TNFR1.

Original languageEnglish
Pages (from-to)410-417
Number of pages8
JournalBone
Volume46
Issue number2
DOIs
StatePublished - Feb 2010

Bibliographical note

Funding Information:
Supported by NIH grant AA12223 (CKL), by NIH National Center for Research Resources Grant # 1CORR16517-01 , and by Arkansas Biosciences Institute (CKL) funded by the Arkansas Tobacco Settlement Plan and administered by Arkansas Children's Hospital Research Institute.

Keywords

  • Distraction osteogenesis
  • Mouse
  • TNF receptors

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Histology

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