iRoot BP Plus promotes osteo/odontogenic differentiation of bone marrow mesenchymal stem cells via MAPK pathways and autophagy

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Abstract

Background

iRoot BP Plus is a novel bioceramic endodontic material. Recently, it has been considered as an alternative to MTA which is the most popular scaffold cover during regenerative endodontic therapy. This study aimed to evaluate the effects of iRoot BP Plus on the osteo/odontogenic capacity of bone marrow mesenchymal stem cells (BMMSCs), including the underlying mechanisms.

Methods

BMMSCs were collected by a whole marrow method and treated with iRoot BP Plus-conditioned medium (BP-CM). The proliferation ability was evaluated by cell counting kit 8 and flow cytometry. Complete medium was used as a blank control, and 2 mg/ml MTA-conditioned medium was served as a positive control. Alkaline phosphatase (ALP) activity assay, ALP staining, western blot, real-time RT-PCR, Alizarin Red S staining, and immunofluorescence staining were performed to explore the osteo/odontogenic potential and the involvement of MAPK pathways. Besides, autophagy was investigated by western blot, immunofluorescence staining, and transmission electron microscopy.

Results

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Most cited references 48

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Autophagy in osteoblasts is involved in mineralization and bone homeostasis.

Marie Nollet, Sabine Santucci-Darmanin, Véronique Breuil … (2014)

Bone remodeling is a tightly controlled mechanism in which osteoblasts (OB), the cells responsible for bone formation, osteoclasts (OC), the cells specialized for bone resorption, and osteocytes, the multifunctional mechanosensing cells embedded in the bone matrix, are the main actors. Increased oxidative stress in OB, the cells producing and mineralizing bone matrix, has been associated with osteoporosis development but the role of autophagy in OB has not yet been addressed. This is the goal of the present study. We first show that the autophagic process is induced in OB during mineralization. Then, using knockdown of autophagy-essential genes and OB-specific autophagy-deficient mice, we demonstrate that autophagy deficiency reduces mineralization capacity. Moreover, our data suggest that autophagic vacuoles could be used as vehicles in OB to secrete apatite crystals. In addition, autophagy-deficient OB exhibit increased oxidative stress and secretion of the receptor activator of NFKB1 (TNFSF11/RANKL), favoring generation of OC, the cells specialized in bone resorption. In vivo, we observed a 50% reduction in trabecular bone mass in OB-specific autophagy-deficient mice. Taken together, our results show for the first time that autophagy in OB is involved both in the mineralization process and in bone homeostasis. These findings are of importance for mineralized tissues which extend from corals to vertebrates and uncover new therapeutic targets for calcified tissue-related metabolic pathologies.

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Autophagy controls mesenchymal stem cell properties and senescence during bone aging

Yang Ma, Meng Qi, Ying An … (2017)

Summary Bone marrow‐derived mesenchymal stem cells (BMMSCs) exhibit degenerative changes, including imbalanced differentiation and reduced proliferation during aging, that contribute to age‐related bone loss. We demonstrate here that autophagy is significantly reduced in aged BMMSCs compared with young BMMSCs. The autophagy inhibitor 3‐methyladenine (3‐MA) could turn young BMMSCs into a relatively aged state by reducing their osteogenic differentiation and proliferation capacity and enhancing their adipogenic differentiation capacity. Accordingly, the autophagy activator rapamycin could restore the biological properties of aged BMMSCs by increasing osteogenic differentiation and proliferation capacity and decreasing adipogenic differentiation capacity. Possible underlying mechanisms were explored, and the analysis revealed that autophagy could affect reactive oxygen species and p53 levels, thus regulating biological properties of BMMSCs. In an in vivo study, we found that activation of autophagy restored bone loss in aged mice. In conclusion, our results suggest that autophagy plays a pivotal role in the aging of BMMSCs, and activation of autophagy could partially reverse this aging and may represent a potential therapeutic avenue to clinically treat age‐related bone loss.

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Runx2: Structure, function, and phosphorylation in osteoblast differentiation.

S Vimalraj, Selva Arumugam, P. J. Miranda … (2015)

Runx2 is a master transcription factor for osteogenesis. The most important phenomenon that makes this protein a master regulator for osteogenesis is its structural integrity. In response to various stimuli, the domains in Runx2 interact with several proteins and regulate a number of cellular events via posttranslational modifications. Hence, in this review we summarized the structural integrity of Runx2 and its posttranslational modifications, especially the phosphorylation responsible for either stimulation or inhibition of its regulatory role in osteogenesis.

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Author and article information

Contributors

Jinhua Yu: 86-25-86862843 , yujinhua@njmu.edu.cn

Journal

Journal ID (nlm-ta): Stem Cell Res Ther

Journal ID (iso-abbrev): Stem Cell Res Ther

Title: Stem Cell Research & Therapy

Publisher: BioMed Central (London )

ISSN (Electronic): 1757-6512

Publication date (Electronic): 29 July 2019

Publication date PMC-release: 29 July 2019

Publication date Collection: 2019

Volume: 10

Electronic Location Identifier: 222

Affiliations

[1 ]ISNI 0000 0000 9255 8984, GRID grid.89957.3a, Key Laboratory of Oral Diseases of Jiangsu Province, Institute of Stomatology, , Nanjing Medical University, ; 136 Hanzhong Road, Nanjing, 210029 Jiangsu China

[2 ]ISNI 0000 0000 9255 8984, GRID grid.89957.3a, Endodontic Department, School of Stomatology, , Nanjing Medical University, ; 136 Hanzhong Road, Nanjing, 210029 Jiangsu China

[3 ]ISNI 0000 0001 2314 964X, GRID grid.41156.37, Nanjing Stomatological Hospital, , Medical School of Nanjing University, ; 30 Zhongyang Road, Nanjing, 210008 Jiangsu China

Article

Publisher ID: 1345

DOI: 10.1186/s13287-019-1345-3

PMC ID: 6664598

PubMed ID: 31358050

SO-VID: f6b26614-cb77-4a17-9048-695a9d9e45ea

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 : 17 May 2019

Date revision received : 30 June 2019

Date accepted : 15 July 2019

Funding

Funded by: National Natural Science Foundation of China

Award ID: 81873707

Award Recipient : Jinhua Yu

Funded by: Medical Talent Project of Jiangsu Province

Award ID: ZDRCA2016086

Award Recipient : Jinhua Yu

Funded by: The Priority Academic Program Development of Jiangsu Higher Education Institutions

Award ID: PAPD, 2018-87

Award Recipient : Jinhua Yu

Funded by: Science and Technology Development Project of Jiangsu Province

Award ID: BE2017731

Award Recipient : Jinhua Yu

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ScienceOpen disciplines: Molecular medicine

Keywords: iroot bp plus,bmmscs,osteo/odontogenic differentiation,autophagy,mapk pathways

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ScienceOpen disciplines: Molecular medicine

Keywords: iroot bp plus, bmmscs, osteo/odontogenic differentiation, autophagy, mapk pathways

iRoot BP Plus promotes osteo/odontogenic differentiation of bone marrow mesenchymal stem cells via MAPK pathways and autophagy

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Abstract

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Most cited references 48

Autophagy in osteoblasts is involved in mineralization and bone homeostasis.

Autophagy controls mesenchymal stem cell properties and senescence during bone aging

Runx2: Structure, function, and phosphorylation in osteoblast differentiation.

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