title: Direct bone formation during distraction osteogenesis does not require TNFalpha receptors and elevated serum TNFalpha fails to inhibit bone formation in TNFR1 deficient mice.
abstract: Distraction osteogenesis (DO) is a process which induces direct new bone formation as a result of mechanical distraction. Tumor necrosis factor-alpha (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 microg/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.
authors.affiliation: Laboratory for Limb Regeneration Research, Arkansas Children's Hospital Research Institute, Little Rock, AR, USA.
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Wahl
authors.forename: James
authors.initials: J
authors.lastname: Aronson
authors.forename: Lichu
authors.initials: L
authors.lastname: Liu
authors.forename: Robert A
authors.initials: RA
authors.lastname: Skinner
authors.forename: Mike J
authors.initials: MJ
authors.lastname: Miller
authors.forename: Gael E
authors.initials: GE
authors.lastname: Cockrell
authors.forename: John L
authors.initials: JL
authors.lastname: Fowlkes
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Thrailkill
authors.forename: Robert C
authors.initials: RC
authors.lastname: Bunn
authors.forename: Martin J J
authors.initials: MJ
authors.lastname: Ronis
authors.forename: Charles K
authors.initials: CK
authors.lastname: Lumpkin
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D010012:Osteogenesis / Q000187:drug effects / Q000502:physiology*; D019857:Osteogenesis, Distraction; D011859:Radiography; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency* / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D013194:Staining and Labeling; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000494:pharmacology*
chemical_list: D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha