Direct bone formation during distraction osteogenesis does not require TNFα receptors and elevated serum TNFα 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-α (TNF) is a cytokine that can modulate osteoblastogenesis. The direct effects of TNF on direct bone formation in rodents are hypothetically mediat...

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Published in:Bone (New York, N.Y.) N.Y.), 2010-02, Vol.46 (2), p.410-417
Main Authors: Wahl, Elizabeth C, Aronson, James, Liu, Lichu, Skinner, Robert A, Miller, Mike J, Cockrell, Gael E, Fowlkes, John L, Thrailkill, Kathryn M, Bunn, Robert C, Ronis, Martin J.J, Lumpkin, Charles K
Format: Article
Language:English
Subjects:
Biological and medical sciences
Cell physiology
Distraction osteogenesis
Fundamental and applied biological sciences. Psychology
Mineralization, calcification
Molecular and cellular biology
Mouse
Orthopedics
Skeleton and joints
TNF receptors
Vertebrates: anatomy and physiology, studies on body, several organs or systems
Vertebrates: osteoarticular system, musculoskeletal system
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Summary: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.
ISSN:8756-3282
1873-2763
DOI:10.1016/j.bone.2009.09.011