SFRP2 enhances the osteogenic differentiation of apical papilla stem cells by antagonizing the canonical WNT pathway

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Abstract

Background

Exploring the molecular mechanisms underlying directed differentiation is helpful in the development of clinical applications of mesenchymal stem cells (MSCs). Our previous study on dental tissue-derived MSCs demonstrated that secreted frizzled-related protein 2 (SFRP2), a Wnt inhibitor, could enhance osteogenic differentiation in stem cells from the apical papilla (SCAPs). However, how SFRP2 promotes osteogenic differentiation of dental tissue-derived MSCs remains unclear. In this study, we used SCAPs to investigate the underlying mechanisms.

Methods

SCAPs were isolated from the apical papilla of immature third molars. Western blot and real-time RT-PCR were applied to detect the expression of β-catenin and Wnt target genes. Alizarin Red staining, quantitative calcium analysis, transwell cultures and in vivo transplantation experiments were used to study the osteogenic differentiation potential of SCAPs.

Results

SFRP2 inhibited canonical Wnt signaling by enhancing phosphorylation and decreasing the expression of nuclear β-catenin in vitro and in vivo . In addition, the target genes of the Wnt signaling pathway, AXIN2 (axin-related protein 2) and MMP7 (matrix metalloproteinase-7), were downregulated by SFRP2. WNT1 inhibited the osteogenic differentiation potential of SCAPs. SFRP2 could rescue this WNT1-impaired osteogenic differentiation potential.

Conclusions

The results suggest that SFRP2 could bind to locally present Wnt ligands and alter the balance of intracellular Wnt signaling to antagonize the canonical Wnt pathway in SCAPs. This elucidates the molecular mechanism underlying the SFRP2-mediated directed differentiation of SCAPs and indicates potential target genes for improving dental tissue regeneration.

Electronic supplementary material

The online version of this article (doi:10.1186/s11658-017-0044-2) contains supplementary material, which is available to authorized users.

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Most cited references 26

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Mesenchymal stem cells derived from dental tissues vs. those from other sources: their biology and role in regenerative medicine.

G Huang, S Gronthos, S. Shi (2009)

To date, 5 different human dental stem/progenitor cells have been isolated and characterized: dental pulp stem cells (DPSCs), stem cells from exfoliated deciduous teeth (SHED), periodontal ligament stem cells (PDLSCs), stem cells from apical papilla (SCAP), and dental follicle progenitor cells (DFPCs). These postnatal populations have mesenchymal-stem-cell-like (MSC) qualities, including the capacity for self-renewal and multilineage differentiation potential. MSCs derived from bone marrow (BMMSCs) are capable of giving rise to various lineages of cells, such as osteogenic, chondrogenic, adipogenic, myogenic, and neurogenic cells. The dental-tissue-derived stem cells are isolated from specialized tissue with potent capacities to differentiate into odontogenic cells. However, they also have the ability to give rise to other cell lineages similar to, but different in potency from, that of BMMSCs. This article will review the isolation and characterization of the properties of different dental MSC-like populations in comparison with those of other MSCs, such as BMMSCs. Important issues in stem cell biology, such as stem cell niche, homing, and immunoregulation, will also be discussed.

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LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development.

Yaoqin Gong, Roger B Slee, Naomi Fukai … (2001)

In humans, low peak bone mass is a significant risk factor for osteoporosis. We report that LRP5, encoding the low-density lipoprotein receptor-related protein 5, affects bone mass accrual during growth. Mutations in LRP5 cause the autosomal recessive disorder osteoporosis-pseudoglioma syndrome (OPPG). We find that OPPG carriers have reduced bone mass when compared to age- and gender-matched controls. We demonstrate LRP5 expression by osteoblasts in situ and show that LRP5 can transduce Wnt signaling in vitro via the canonical pathway. We further show that a mutant-secreted form of LRP5 can reduce bone thickness in mouse calvarial explant cultures. These data indicate that Wnt-mediated signaling via LRP5 affects bone accrual during growth and is important for the establishment of peak bone mass.

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High bone density due to a mutation in LDL-receptor-related protein 5.

Lynn Boyden, Junhao Mao, Joseph Belsky … (2002)

Osteoporosis is a major public health problem of largely unknown cause. Loss-of-function mutations in the gene for low-density lipoprotein receptor-related protein 5 (LRP5), which acts in the Wnt signaling pathway, have been shown to cause osteoporosis-pseudoglioma. We performed genetic and biochemical analyses of a kindred with an autosomal dominant syndrome characterized by high bone density, a wide and deep mandible, and torus palatinus. Genetic analysis revealed linkage of the syndrome to chromosome 11q12-13 (odds of linkage, >1 million to 1), an interval that contains LRP5. Affected members of the kindred had a mutation in this gene, with valine substituted for glycine at codon 171 (LRP5V171). This mutation segregated with the trait in the family and was absent in control subjects. The normal glycine lies in a so-called propeller motif that is highly conserved from fruit flies to humans. Markers of bone resorption were normal in the affected subjects, whereas markers of bone formation such as osteocalcin were markedly elevated. Levels of fibronectin, a known target of signaling by Wnt, a developmental protein, were also elevated. In vitro studies showed that the normal inhibition of Wnt signaling by another protein, Dickkopf-1 (Dkk-1), was defective in the presence of LRP5V171 and that this resulted in increased signaling due to unopposed Wnt activity. The LRP5V171 mutation causes high bone density, with a thickened mandible and torus palatinus, by impairing the action of a normal antagonist of the Wnt pathway and thus increasing Wnt signaling. These findings demonstrate the role of altered LRP5 function in high bone mass and point to Dkk as a potential target for the prevention or treatment of osteoporosis.

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Author and article information

Contributors

Zhaochen Shan: +86 10 6706 2012 , shanzhch629@163.com

Journal

Journal ID (nlm-ta): Cell Mol Biol Lett

Journal ID (iso-abbrev): Cell. Mol. Biol. Lett

Title: Cellular & Molecular Biology Letters

Publisher: BioMed Central (London )

ISSN (Print): 1425-8153

ISSN (Electronic): 1689-1392

Publication date (Electronic): 8 August 2017

Publication date PMC-release: 8 August 2017

Publication date Collection: 2017

Volume: 22

Electronic Location Identifier: 14

Affiliations

[1 ]ISNI 0000 0004 0369 153X, GRID grid.24696.3f, Laboratory of Molecular Signaling and Stem Cells Therapy, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, , Capital Medical University School of Stomatology, ; No. 4 Tiantanxili, Dongcheng District, Beijing, 100050 China

[2 ]ISNI 0000 0004 0369 153X, GRID grid.24696.3f, Department of Implant Dentistry, , Capital Medical University School of Stomatology, ; Beijing, 100050 China

[3 ]ISNI 0000 0004 0369 153X, GRID grid.24696.3f, Molecular Laboratory for Gene Therapy and Tooth Regeneration, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, , Capital Medical University School of Stomatology, ; No. 4 Tiantanxili, Dongcheng District, Beijing, 100050 China

[4 ]ISNI 0000 0004 0369 153X, GRID grid.24696.3f, Department of Stomatology, Beijing Children’s Hospital, , Capital Medical University, ; No.56 Nanlishi Road, Xicheng District, Beijing, 100045 China

[5 ]ISNI 0000 0004 0369 153X, GRID grid.24696.3f, Department of Biochemistry and Molecular Biology, , Capital Medical University School of Basic Medical Sciences, ; No. 10 Xitoutiao Youanmen, Fengtai District, Beijing, 100069 China

[6 ]ISNI 0000 0004 0369 153X, GRID grid.24696.3f, Department of Stomatology, Beijing Shijitan Hospital, , Capital Medical University, ; Beijing, 100045 China

[7 ]ISNI 0000 0004 0369 153X, GRID grid.24696.3f, Oral and Maxillofacial Surgery Department, , Capital Medical University School of Stomatology, ; No. 4 Tiantanxili, Dongcheng District, Beijing, 100050 China

Article

Publisher ID: 44

DOI: 10.1186/s11658-017-0044-2

PMC ID: 5547503

PubMed ID: 28794794

SO-VID: 6c16b45f-dab0-4afd-ae0d-76ee66ef670a

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 2 February 2017

Date accepted : 17 July 2017

Funding

Funded by: National Natural Science Foundation of China (CN)

Award ID: 81400527

Award Recipient : Luyuan Jin

Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;

Award ID: 81670948

Award Recipient : Yu Cao

Funded by: Beijing Municipal Administration of Hospitals’ Youth Programm

Award ID: QML20151402

Award Recipient : Luyuan Jin

Funded by: 2016 QNRC001Young Elite Scientist Sponsorship Program by CAST

Award ID: 2016 QNRC001

Award Recipient : Luyuan Jin

Custom metadata

Keywords: sfrp2,osteogenic differentiation,stem cells from apical papilla (scaps),wnt signaling,β-catenin

Data availability:

Keywords: sfrp2, osteogenic differentiation, stem cells from apical papilla (scaps), wnt signaling, β-catenin

SFRP2 enhances the osteogenic differentiation of apical papilla stem cells by antagonizing the canonical WNT pathway

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Abstract

Background

Methods

Results

Conclusions

Electronic supplementary material

Related collections

Stress signalling in stem cells

Most cited references 26

Mesenchymal stem cells derived from dental tissues vs. those from other sources: their biology and role in regenerative medicine.

LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development.

High bone density due to a mutation in LDL-receptor-related protein 5.

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