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Bone Abstracts (2016) 5 P146 | DOI: 10.1530/boneabs.5.P146

ECTS2016 Poster Presentations Cell biology: osteoblasts and bone formation (36 abstracts)

Pharmacological activation of the non-canonical TGF-β signaling is a novel strategy to enhance bone formation

Abbas Jafari 1, , Majken Siersbaek 2 , Li Chen 2 & Moustapha Kassem 1,

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1Institute of Cellular & Molecular Medicine, Danish Stem Cell Center, University of Copenhagen, Copenhagen, Denmark; 2Laboratory of Molecular Endocrinology (KMEB), Department of Endocrinology and Metabolism, Odense University Hospital, Odense, Denmark.


Identifying novel approaches for enhancing osteoblast (OB) differentiation of human skeletal (mesenchymal) stem cells (hMSC) can lead to development of novel anabolic agents required for efficient bone formation. Transforming growth factor-βs (TGF-β1, 2, 3) are one of the most abundant growth factors in bone and play a key role in regulating bone remodeling. Canonical TGF-β signaling inhibits, whereas components of the non-canonical TGF-β signaling (e.g. Akt, P38, ERK) are known to enhance OB differentiation and bone formation. We have identified a small molecule kinase inhibitor H-8, that enhances the ex vivo OB differentiation and in vivo bone formation by hMSC through activation of non-canonical TGF-β signaling. Adding TGF-β1, 2, 3 to hMSC cultures inhibited OB differentiation, as shown by quantification of alkaline phosphatase (ALP) activity. However, in the presence of H-8, TGF-β 1, 2, 3 enhanced OB differentiation of hMSC. Using Active-site-directed competition kinase binding assay, we show that H-8 inhibited the activity of protein kinase G1, which inhibited activation of RhoA-Akt signaling by TGF-β receptor. Western blot analysis showed that TGF-β3 treatment of hMSC reduced levels of phosphorylated Akt (S473), whereas in the presence of H-8, TGF-β3 treatment enhanced Akt phosphorylation. In addition, pharmacological inhibition of Akt (using Triciribine) or TGF-β receptor (using SB505124, SB431542) abolished the enhancing effect of H-8 on OB differentiation. Our data demonstrate that pharmacological activation of non-canonical TGFβ signalling is a novel strategy to develop anabolic drugs for enhancing bone formation. H-8 has the potential to be developed into a drug to be used for enhancing osteoblastic bone formation required for treatment of localized bone defects.

Volume 5

43rd Annual European Calcified Tissue Society Congress

Rome, Italy
14 May 2016 - 17 May 2016

European Calcified Tissue Society 

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