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Assay Drug Dev Technol. 2019 Feb/Mar;17(2):77-88. doi: 10.1089/adt.2018.876. Epub 2019 Jan 9.

Repositioning Tacrolimus: Evaluation of the Effect of Short-Term Tacrolimus Treatment on Osteoprogenitor Cells and Primary Cells for Bone Regenerative Engineering.

O'Neill E1,2,3, Rajpura K1,2,4, Carbone EJ1,2,3,5, Awale G1,2, Kan HM1,2,6, Lo KW1,2,3,4,5,7.

Author information

1
1 Institute for Regenerative Engineering, University of Connecticut Health Center, School of Medicine, Farmington, Connecticut.
2
2 The Raymond and Beverly Sackler Center for Biomedical, Biological, Physical and Engineering Sciences, University of Connecticut Health Center, School of Medicine, Farmington, Connecticut.
3
3 Division of Endocrinology, Department of Medicine, University of Connecticut Health Center, School of Medicine, Farmington, Connecticut.
4
4 Connecticut Institute for Clinical and Translational Science, University of Connecticut Health Center, Farmington, Connecticut.
5
5 UConn Stem Cell Institute, University of Connecticut Health Center, Farmington, Connecticut.
6
6 Department of Orthopaedic Surgery, University of Connecticut Health Center, School of Medicine, Farmington, Connecticut.
7
7 Department of Biomedical Engineering, University of Connecticut, School of Engineering, Storrs, Connecticut.

Abstract

Small-molecule-based bone regenerative engineering is an encouraging strategy for repair and regeneration of skeletal tissue. Using osteogenic small molecules for engineering bone tissue has several potential benefits over polypeptide-based approaches. Interestingly, hundreds of such small molecules possess the capability to promote osteogenesis, and several of these are already approved by the FDA for use in other applications, indicating their safety for human use. However, the need for their use at a high frequency and/or duration, due to their short half-life and nonspecificity, is still problematic. We, and others, have identified several non-FDA-approved small-molecule-based compounds that induce long-lasting osteogenic effects following short-term (<24 h) treatment. In this study, however, we have performed a proactive screen to investigate and compare the osteogenic effects of several preselected FDA-approved small-molecule drugs in vitro using osteoprogenitor MC3T3-E1 cells. Our results demonstrate that treatment with the small-molecule drug tacrolimus (FK-506) for 24 h significantly enhanced long-lasting osteogenic responses in both osteoprogenitor cells and primary cell cultures. In addition, we tested whether a short-term treatment with FK-506 is able to induce osteogenic differentiation of cells seeded on a polymeric scaffold in vitro. Using an osteogenic small molecule that has long-lasting effects despite a short duration of exposure to cells may alleviate the undesirable effects often seen with many osteogenic small molecules.

KEYWORDS:

bone regeneration; drug delivery; drug repositioning; regenerative engineering; small molecules; tacrolimus

PMID:
30624955
DOI:
10.1089/adt.2018.876

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