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The Glycogen Synthase Kinase-3β Inhibitor LSN 2105786 Promotes Zebrafish Fin Regeneration

1
Department of Biology, Indiana University-Purdue University Indianapolis, Indianapolis, IN 46202, USA
2
Lilly Research Laboratories, Indianapolis, IN 46225, USA
3
Novartis Institute for BioMedical Research, Cambridge, MA 02139, USA
4
Molecular Templates, Austin, TX 78729, USA
*
Author to whom correspondence should be addressed.
Biomedicines 2019, 7(2), 30; https://doi.org/10.3390/biomedicines7020030
Received: 22 March 2019 / Revised: 12 April 2019 / Accepted: 14 April 2019 / Published: 19 April 2019
(This article belongs to the Special Issue Zebrafish Models for Development and Disease)
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Abstract

The Wnt pathway has been shown to regulate bone homeostasis and to influence some bone disease states. We utilized a zebrafish model system to study the effects of a synthetic, orally bioavailable glycogen synthase kinase-3β (GSK3β) inhibitor LSN 2105786, which activates Wnt signaling during bone healing and embryogenesis. GSK3β inhibitor treatment was used to phenocopy GSK3β morpholino oligonucleotide (MO) knockdown in zebrafish embryos. Human and zebrafish synthetic mRNA injection were similarly effective at rescue of GSK3β MO knockdown. During caudal fin regeneration, bony rays are the first structure to differentiate in zebrafish fins, providing a useful model to study bone healing. Caudal fin regeneration experiments were conducted using various concentrations of a GSK3β inhibitor, examining duration and concentration dependence on regenerative outgrowth. Experiments revealed continuous low concentration (4–5 nM) treatment to be more effective at increasing regeneration than intermittent dosing. Higher concentrations inhibited fin growth, perhaps by excessive stimulation of differentiation programs. Increased Wnt responsive gene expression and differentiation were observed in response to GSK3b inhibitor treatment. Activating Wnt signaling also increased cell proliferation and osteoblast differentiation in fin regenerates. Together, these data indicate that bone healing in zebrafish fin regeneration was improved by activating Wnt signaling using GSK3b inhibitor treatment. In addition, caudal fin regeneration is useful to evaluate dose-dependent pharmacological efficacy in bone healing, various dosing regimens and possible toxicological effects of compounds. View Full-Text
Keywords: zebrafish; glycogen synthase kinase-3β; bone healing; regeneration; caudal fin zebrafish; glycogen synthase kinase-3β; bone healing; regeneration; caudal fin
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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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Sarmah, S.; Curtis, C.; Mahin, J.; Farrell, M.; Engler, T.A.; Sanchez-Felix, M.V.; Sato, M.; Ma, Y.L.; Chu, S.; Marrs, J.A. The Glycogen Synthase Kinase-3β Inhibitor LSN 2105786 Promotes Zebrafish Fin Regeneration. Biomedicines 2019, 7, 30.

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