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Back to 2017 Program


Modulating TAK1 Signaling to Enhance Scaffold and Cell-Free Calvarial Healing
Hsiao Hsin Sung DDS, David Cholok BS, Michael T. Chung, M.D., Kavitha Ranganathan, M.D., Joseph Habbouche, BS, Christopher Breuler, BS, John Butts, BS, Arminder Kaura, BS, John Li, M.D., Shawn Loder, M.D., D, Serra Ucer, PhD., Caitlin Priest, BS, Shuli Li, PhD., Jonathan Reimer, BS, Yuji Mishina, PhD., Steven R. Buchman, M.D., Shailesh Agarwal, M.D., Benjamin Levi, MD.
University of Michigan, Ann Arbor, MI, USA.

PURPOSE Bone tissue engineering remains hampered by inadequate scaffold design and regulatory limitations on autologous cell use. We developed a novel system to silence and reactivate TGF-ß activating kinase 1 (TAK1), which mediates TGF-β1 and BMP2. We hypothesize that Tak1 can be initially silenced to increase local cell proliferation followed by Tak1 reactivation to stimulate bone differentiation, providing scaffold and cell-free bone healing.
METHODS We developed a novel dual-recombinase system (Cre/lox; FLP/FRT) to allow silencing and reactivation of Tak1. Critical sized-calvarial defects were performed and mice received: 1. Ad.LacZ (control) 2. Ad.Cre (knockout) or 3. Ten days Ad.Cre (knockout) followed by Ad.FLP (reactivation) to modulate Tak1 expression. Cellular proliferation and differentiation were quantified histologically. MicroCT was used to quantify bone healing. In vitro studies with calvarial osteoblasts confirmed these findings.
RESULTS
Loss of Tak1 with Ad.Cre increased cellular proliferation (Ki67 immunostaining; Fig. 1A) while suppressing osteogenesis (Osterix immunostaining) within the defect. Ad.Cre followed by Ad.FLP stimulated increased cell proliferation followed by enhanced osteogenic differentiation. Timed Tak1 suppression followed by Tak1 activation improved bone healing compared to controls by microCT quantification. In vitro results (Fig. 1B, 1C) with calvarial osteoblasts were consistent with in vivo findings.
CONCLUSIONS
These results validate that TAK1 can be mediated therapeutically to first potentiate cellular proliferation and then stimulate osteogenic differentiation to maximize bone healing without introducing exogenous scaffolds or cells.


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