Cargando…

Sustained release of a highly specific GSK3β inhibitor SB216763 in the PCL scaffold creates an osteogenic niche for osteogenesis, anti-adipogenesis, and potential angiogenesis

The safe and effective use of Wnt signaling is a hot topic in developing osteogenic drugs. SB216763 (S33) is a widely used highly specific GSK3β inhibitor. Here, we show that S33 initiates canonical Wnt signaling by inhibiting GSK3β activity in the bone marrow stromal cell line ST2 and increases ost...

Descripción completa

Detalles Bibliográficos
Autores principales: Gong, Weimin, Li, Molin, Zhao, Lizhou, Wang, Pengtao, Wang, Xiaofang, Wang, Bo, Liu, Xing, Tu, Xiaolin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10419179/
https://www.ncbi.nlm.nih.gov/pubmed/37576993
http://dx.doi.org/10.3389/fbioe.2023.1215233
_version_ 1785088452774068224
author Gong, Weimin
Li, Molin
Zhao, Lizhou
Wang, Pengtao
Wang, Xiaofang
Wang, Bo
Liu, Xing
Tu, Xiaolin
author_facet Gong, Weimin
Li, Molin
Zhao, Lizhou
Wang, Pengtao
Wang, Xiaofang
Wang, Bo
Liu, Xing
Tu, Xiaolin
author_sort Gong, Weimin
collection PubMed
description The safe and effective use of Wnt signaling is a hot topic in developing osteogenic drugs. SB216763 (S33) is a widely used highly specific GSK3β inhibitor. Here, we show that S33 initiates canonical Wnt signaling by inhibiting GSK3β activity in the bone marrow stromal cell line ST2 and increases osteoblast marker alkaline phosphatase activity, osteoblast marker gene expression including Alpl, Col1α1, and Runx2, promoting osteogenic differentiation and mineralization of ST2 cells. In addition, S33 suppressed the expression of adipogenic transcription factors Pparg and Cebpa in ST2 cells to suppress adipogenesis. ICRT-14, a specific transcriptional inhibitor of Wnt signaling, reversed the effects of S33 on the differentiation of ST2 cells. S33 also increased the expression of osteoclast cytokines RANKL and Opg but decreased the RANKL/Opg ratio and had the potential to inhibit osteoclast differentiation. In addition, we printed the PSCI3D (polycaprolactone, S33, cell-integrated 3D) scaffolds using a newly established integrated 3D printing system for hard materials and cells. S33 sustained release in the hydrogel of the scaffold with 25.4% release on day 1% and 81.7% release over 7 days. Cells in the scaffolds had good cell viability. The ratio of live/dead cells remained above 94% for 7 days, while the cells in the scaffolds proliferated linearly, and the proliferative activity of the PSCI3D scaffold group increased 1.4-fold and 1.7-fold on days 4 and 7, respectively. Similarly, in PSCI3D scaffolds, osteogenic differentiation of st2 cells was increased. The alkaline phosphatase activity increased 1.4- and 4.0-fold on days 7 and 14, respectively, and mineralization increased 1.7-fold at 21 days. In addition, PSCI3D conditioned medium promoted migration and tubulogenesis of HUVECs, and S33 upregulated the expression of Vegfa, a key factor in angiogenesis. In conclusion, our study suggests that S33 functions in osteogenesis, anti-adipogenesis, and potential inhibition of osteoclast differentiation. And the sustained release of S33 in PSCI3D scaffolds creates a safe osteogenic niche, which promotes cell proliferation, osteogenesis, and angiogenesis and has application prospects.
format Online
Article
Text
id pubmed-10419179
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-104191792023-08-12 Sustained release of a highly specific GSK3β inhibitor SB216763 in the PCL scaffold creates an osteogenic niche for osteogenesis, anti-adipogenesis, and potential angiogenesis Gong, Weimin Li, Molin Zhao, Lizhou Wang, Pengtao Wang, Xiaofang Wang, Bo Liu, Xing Tu, Xiaolin Front Bioeng Biotechnol Bioengineering and Biotechnology The safe and effective use of Wnt signaling is a hot topic in developing osteogenic drugs. SB216763 (S33) is a widely used highly specific GSK3β inhibitor. Here, we show that S33 initiates canonical Wnt signaling by inhibiting GSK3β activity in the bone marrow stromal cell line ST2 and increases osteoblast marker alkaline phosphatase activity, osteoblast marker gene expression including Alpl, Col1α1, and Runx2, promoting osteogenic differentiation and mineralization of ST2 cells. In addition, S33 suppressed the expression of adipogenic transcription factors Pparg and Cebpa in ST2 cells to suppress adipogenesis. ICRT-14, a specific transcriptional inhibitor of Wnt signaling, reversed the effects of S33 on the differentiation of ST2 cells. S33 also increased the expression of osteoclast cytokines RANKL and Opg but decreased the RANKL/Opg ratio and had the potential to inhibit osteoclast differentiation. In addition, we printed the PSCI3D (polycaprolactone, S33, cell-integrated 3D) scaffolds using a newly established integrated 3D printing system for hard materials and cells. S33 sustained release in the hydrogel of the scaffold with 25.4% release on day 1% and 81.7% release over 7 days. Cells in the scaffolds had good cell viability. The ratio of live/dead cells remained above 94% for 7 days, while the cells in the scaffolds proliferated linearly, and the proliferative activity of the PSCI3D scaffold group increased 1.4-fold and 1.7-fold on days 4 and 7, respectively. Similarly, in PSCI3D scaffolds, osteogenic differentiation of st2 cells was increased. The alkaline phosphatase activity increased 1.4- and 4.0-fold on days 7 and 14, respectively, and mineralization increased 1.7-fold at 21 days. In addition, PSCI3D conditioned medium promoted migration and tubulogenesis of HUVECs, and S33 upregulated the expression of Vegfa, a key factor in angiogenesis. In conclusion, our study suggests that S33 functions in osteogenesis, anti-adipogenesis, and potential inhibition of osteoclast differentiation. And the sustained release of S33 in PSCI3D scaffolds creates a safe osteogenic niche, which promotes cell proliferation, osteogenesis, and angiogenesis and has application prospects. Frontiers Media S.A. 2023-07-28 /pmc/articles/PMC10419179/ /pubmed/37576993 http://dx.doi.org/10.3389/fbioe.2023.1215233 Text en Copyright © 2023 Gong, Li, Zhao, Wang, Wang, Wang, Liu and Tu. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Bioengineering and Biotechnology
Gong, Weimin
Li, Molin
Zhao, Lizhou
Wang, Pengtao
Wang, Xiaofang
Wang, Bo
Liu, Xing
Tu, Xiaolin
Sustained release of a highly specific GSK3β inhibitor SB216763 in the PCL scaffold creates an osteogenic niche for osteogenesis, anti-adipogenesis, and potential angiogenesis
title Sustained release of a highly specific GSK3β inhibitor SB216763 in the PCL scaffold creates an osteogenic niche for osteogenesis, anti-adipogenesis, and potential angiogenesis
title_full Sustained release of a highly specific GSK3β inhibitor SB216763 in the PCL scaffold creates an osteogenic niche for osteogenesis, anti-adipogenesis, and potential angiogenesis
title_fullStr Sustained release of a highly specific GSK3β inhibitor SB216763 in the PCL scaffold creates an osteogenic niche for osteogenesis, anti-adipogenesis, and potential angiogenesis
title_full_unstemmed Sustained release of a highly specific GSK3β inhibitor SB216763 in the PCL scaffold creates an osteogenic niche for osteogenesis, anti-adipogenesis, and potential angiogenesis
title_short Sustained release of a highly specific GSK3β inhibitor SB216763 in the PCL scaffold creates an osteogenic niche for osteogenesis, anti-adipogenesis, and potential angiogenesis
title_sort sustained release of a highly specific gsk3β inhibitor sb216763 in the pcl scaffold creates an osteogenic niche for osteogenesis, anti-adipogenesis, and potential angiogenesis
topic Bioengineering and Biotechnology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10419179/
https://www.ncbi.nlm.nih.gov/pubmed/37576993
http://dx.doi.org/10.3389/fbioe.2023.1215233
work_keys_str_mv AT gongweimin sustainedreleaseofahighlyspecificgsk3binhibitorsb216763inthepclscaffoldcreatesanosteogenicnicheforosteogenesisantiadipogenesisandpotentialangiogenesis
AT limolin sustainedreleaseofahighlyspecificgsk3binhibitorsb216763inthepclscaffoldcreatesanosteogenicnicheforosteogenesisantiadipogenesisandpotentialangiogenesis
AT zhaolizhou sustainedreleaseofahighlyspecificgsk3binhibitorsb216763inthepclscaffoldcreatesanosteogenicnicheforosteogenesisantiadipogenesisandpotentialangiogenesis
AT wangpengtao sustainedreleaseofahighlyspecificgsk3binhibitorsb216763inthepclscaffoldcreatesanosteogenicnicheforosteogenesisantiadipogenesisandpotentialangiogenesis
AT wangxiaofang sustainedreleaseofahighlyspecificgsk3binhibitorsb216763inthepclscaffoldcreatesanosteogenicnicheforosteogenesisantiadipogenesisandpotentialangiogenesis
AT wangbo sustainedreleaseofahighlyspecificgsk3binhibitorsb216763inthepclscaffoldcreatesanosteogenicnicheforosteogenesisantiadipogenesisandpotentialangiogenesis
AT liuxing sustainedreleaseofahighlyspecificgsk3binhibitorsb216763inthepclscaffoldcreatesanosteogenicnicheforosteogenesisantiadipogenesisandpotentialangiogenesis
AT tuxiaolin sustainedreleaseofahighlyspecificgsk3binhibitorsb216763inthepclscaffoldcreatesanosteogenicnicheforosteogenesisantiadipogenesisandpotentialangiogenesis