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Non-canonical BMP Signaling Regulates Endochondral Bone Development and Trauma-induced Heterotopic Ossification
Hsiao Hsin Sung, DDS, Shailesh Agarwal, MD, Shawn Loder, BS, James Drake, BS, David Cholok, BS, John Li, MD, Kavitha Ranganathan, MD, Shuli Li, MD, Yuji Mishina, PhD, Benjamin Levi, MD.
University of Michigan, Ann Arbor, MI, USA.

PURPOSE: Canonical BMP signaling plays a central role in endochondral bone development and trauma-induced heterotopic ossification (HO). However, the role of non-canonical BMP signaling through the TGF--activated kinase (TAK1) pathway has not been evaluated in HO. We hypothesize that the TAK1 pathway is crucial for endochondral bone development and HO.
METHODS: Cre-conditional TAK1 knockout mice (Prx1-Cre;Tak1fl/fl) growth plates were evaluated during early post-natal development (P3-P8). Tamoxifen inducible TAK1 knockout (Ubi.CreERT;Tak1fl/fl) and Prx1-Cre;Tak1fl/fl mice and littermate controls underwent Achilles’ tenotomy with 30% TBSA. MicroCT imaging, histological analysis, osteogenic differentiation and RNA/protein analysis were performed to assess the TAK1 pathway in the cartilaginous HO.
RESULTS: Ubi.CreERT;Tak1fl/fl mice formed 30% less ectopic bone compared to control 9 weeks after burn/tenotomy (p<0.05) (A). Prx1-Cre;Tak1fl/fl mice exhibit smaller tibia bone size, more immature proliferating chondrocytes, and disorganization of mature bone. Mesenchymal cells isolated from tamoxifen-inducible Tak1 knockout mice showed decreased osteogenic and chondrogenic potential as compared to cells from littermates (B,C). In vitro inhibition with TAK1 inhibitor NG-25 similarly significantly reduced chondrogenic and osteogenic differentiation (p<0.05) (D).
CONCLUSIONS: TAK1 plays a prominent role in chondrogenesis during limb development and ectopic bone formation, confirmed by abnormal bone growth and diminished HO in knockout mice. NG-25 appears to be a candidate drug for TAK1 inhibition, which we will evaluate for treatment of HO using our burn/tenotomy model.


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