Cargando…

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

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 ost...

Descripción completa

Detalles Bibliográficos
Autores principales: Sangadala, Sreedhara, Devereaux, Emily J., Presciutti, Steven M., Boden, Scott D., Willet, Nick J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6515024/
https://www.ncbi.nlm.nih.gov/pubmed/30999619
http://dx.doi.org/10.3390/ijms20081900
_version_ 1783417996538019840
author Sangadala, Sreedhara
Devereaux, Emily J.
Presciutti, Steven M.
Boden, Scott D.
Willet, Nick J.
author_facet Sangadala, Sreedhara
Devereaux, Emily J.
Presciutti, Steven M.
Boden, Scott D.
Willet, Nick J.
author_sort Sangadala, Sreedhara
collection PubMed
description 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.
format Online
Article
Text
id pubmed-6515024
institution National Center for Biotechnology Information
language English
publishDate 2019
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-65150242019-05-30 FK506 Induces Ligand-Independent Activation of the Bone Morphogenetic Protein Pathway and Osteogenesis Sangadala, Sreedhara Devereaux, Emily J. Presciutti, Steven M. Boden, Scott D. Willet, Nick J. Int J Mol Sci Article 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. MDPI 2019-04-17 /pmc/articles/PMC6515024/ /pubmed/30999619 http://dx.doi.org/10.3390/ijms20081900 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Sangadala, Sreedhara
Devereaux, Emily J.
Presciutti, Steven M.
Boden, Scott D.
Willet, Nick J.
FK506 Induces Ligand-Independent Activation of the Bone Morphogenetic Protein Pathway and Osteogenesis
title FK506 Induces Ligand-Independent Activation of the Bone Morphogenetic Protein Pathway and Osteogenesis
title_full FK506 Induces Ligand-Independent Activation of the Bone Morphogenetic Protein Pathway and Osteogenesis
title_fullStr FK506 Induces Ligand-Independent Activation of the Bone Morphogenetic Protein Pathway and Osteogenesis
title_full_unstemmed FK506 Induces Ligand-Independent Activation of the Bone Morphogenetic Protein Pathway and Osteogenesis
title_short FK506 Induces Ligand-Independent Activation of the Bone Morphogenetic Protein Pathway and Osteogenesis
title_sort fk506 induces ligand-independent activation of the bone morphogenetic protein pathway and osteogenesis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6515024/
https://www.ncbi.nlm.nih.gov/pubmed/30999619
http://dx.doi.org/10.3390/ijms20081900
work_keys_str_mv AT sangadalasreedhara fk506inducesligandindependentactivationofthebonemorphogeneticproteinpathwayandosteogenesis
AT devereauxemilyj fk506inducesligandindependentactivationofthebonemorphogeneticproteinpathwayandosteogenesis
AT presciuttistevenm fk506inducesligandindependentactivationofthebonemorphogeneticproteinpathwayandosteogenesis
AT bodenscottd fk506inducesligandindependentactivationofthebonemorphogeneticproteinpathwayandosteogenesis
AT willetnickj fk506inducesligandindependentactivationofthebonemorphogeneticproteinpathwayandosteogenesis