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United States Department of Agriculture

Agricultural Research Service

Research Project: IMPACT OF EARLY DIETARY FACTORS ON CHILD DEVELOPMENT AND HEALTH

Location: Arkansas Children's Nutrition Center

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

Authors
item Wahl, Elizabeth -
item Aronson, James -
item Liu, Lichu -
item Skinner, Roberts -
item Miller, Mike -
item Cockrell, Gael -
item Fowlkes, John -
item Thrailkill, Kathryn -
item Bunn, Robert -
item Ronis, Martin -
item Lumpkin, Charles -

Submitted to: Bone
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: September 11, 2009
Publication Date: February 15, 2010
Citation: Wahl, E.C., Aronson, J., Liu, L., Skinner, R.A., Miller, M.J., Cockrell, G.E., Fowlkes, J.L., Thrailkill, K.M., Bunn, R.C., Ronis, M.J., Lumpkin, C.K. 2010. Direct bone formation during distraction osteogenesis does not require TNF alpha receptors and elevated serum TNF alpha fails to inhibit bone formation in TNFR1 deficient mice. Bone. 46(2):410-417.

Interpretive Summary: When the human body is attacked by bacteria, viruses, etc., one way it responds is by making specific proteins that are released from the cells and circulate in the blood where they can bind to other cells and alert them of the attack. Once the foreign invader is cleared the levels of these proteins go back to normal. However, if the protein levels stay elevated then they begin to damage the body they were intended to protect. Tumor Necrosie Factor-Alpha (TNF)is one such protein. This protein can bind to cells by locking onto one of two cell surface proteins. This paper shows that the negative effects of too much TNF are due to binding to just one cell protein: TNF receptor 1. It further shows that if we can block this binding we can block the negative effects of excess TNF.

Technical 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 micro g/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.

Last Modified: 8/29/2014