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Int J Mol Sci. 2019 Apr 17;20(8). pii: E1900. doi: 10.3390/ijms20081900.

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

Author information

1
Atlanta VA Medical Center, Decatur, GA 30033, USA. ssangad@emory.edu.
2
Department of Orthopaedics, Emory University School of Medicine, Atlanta, GA 30322, USA. ssangad@emory.edu.
3
Department of Orthopaedics, Emory University School of Medicine, Atlanta, GA 30322, USA. emily.foerster@emory.edu.
4
Atlanta VA Medical Center, Decatur, GA 30033, USA. steven.presciutti@emory.edu.
5
Department of Orthopaedics, Emory University School of Medicine, Atlanta, GA 30322, USA. steven.presciutti@emory.edu.
6
Department of Orthopaedics, Emory University School of Medicine, Atlanta, GA 30322, USA. sboden@emory.edu.
7
Atlanta VA Medical Center, Decatur, GA 30033, USA. nick.willett@emory.edu.
8
Department of Orthopaedics, Emory University School of Medicine, Atlanta, GA 30322, USA. nick.willett@emory.edu.

Abstract

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.

KEYWORDS:

BMP-2; osteogenesis; small molecule; tacrolimus

PMID:
30999619
PMCID:
PMC6515024
DOI:
10.3390/ijms20081900
[Indexed for MEDLINE]
Free PMC Article

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