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Int. J. Mol. Sci. 2019, 20(8), 1900;

FK506 Induces Ligand-Independent Activation of the Bone Morphogenetic Protein Pathway and Osteogenesis

Atlanta VA Medical Center, Decatur, GA 30033, USA
Department of Orthopaedics, Emory University School of Medicine, Atlanta, GA 30322, USA
Authors to whom correspondence should be addressed.
Received: 29 March 2019 / Revised: 12 April 2019 / Accepted: 12 April 2019 / Published: 17 April 2019
(This article belongs to the Special Issue Biomaterials for Bone Tissue Engineering)
PDF [4939 KB, uploaded 17 April 2019]


Osteoinductive bone morphogenetic proteins (BMPs), including BMP-2, have a unique capability of mediating bone formation both in orthotopic and ectopic locations. Immunosuppresive macrolides have been shown to potentiate BMP-2 activity through FKBP12, but these have yet to translate to effective osteoinductive therapies. Herein, we show the osteogenic activity of FK506 as a stand-alone agent in direct comparison to BMP-2 both in vitro and in vivo. FK506 was capable of producing stand-alone alkaline phosphatase induction in C2C12 cells comparable to that seen with rhBMP-2. FK506 treatment activated the BMP receptor, as shown by increased pSmad1/5 levels, and produced significantly higher mRNA levels of the early response genes in BMP and TGF-β pathways. Additionally, the FK506 induction of alkaline phosphatase was shown to be resistant to Noggin treatment. In vivo osteogenic activity of FK506 was tested by local delivery on a collagen sponge in an ectopic subcutaneous implantation model in the rat. Dose responses of FK506 showed increasing levels of ectopic mineralization comparable to the mineral volume produced by BMP-2 delivery. These findings suggest that the use of FK506 can enhance osteoblastic differentiation in vitro and can induce mineralization when delivered locally in vivo. View Full-Text
Keywords: BMP-2; tacrolimus; osteogenesis; small molecule BMP-2; tacrolimus; osteogenesis; small molecule

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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Sangadala, S.; Devereaux, E.J.; Presciutti, S.M.; Boden, S.D.; Willet, N.J. FK506 Induces Ligand-Independent Activation of the Bone Morphogenetic Protein Pathway and Osteogenesis. Int. J. Mol. Sci. 2019, 20, 1900.

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