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Bone Development and Regeneration
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Bone Development and Regeneration

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 January 2021) | Viewed by 51176

Special Issue Editor

Dr. Roman Thaler

E-Mail
Guest Editor
Department of Orthopedic Surgery, Mayo Clinic, MN, USA
Interests: musculoskeletal regeneration; bone development and homeostasis; mesenchymal stem cell differentiation; osteoblastic differentiation; epigenetics

Special Issue Information

Bone is a fascinating tissue conferring structural body support, mechanical integrity, and organ protection. A more holistic perspective accommodates bone as an integral organ that together with other tissues not only regulates mineral homeostasis and maintains the hematopoietic niche but also acts as an endocrine organ to contribute and regulate numerous metabolic processes that are independent of mineral metabolism.

Bone formation is orchestrated by multiple stimuli and processes and based on their embryological origin, ossification of collagenous tissues is regulated by different paths. Compared to other musculoskeletal tissues, bone has a high regenerative potential, with the skeleton being fully remodeled multiple times throughout the human lifespan. However, with a continuous extension of live expectancy, aging-related bone issues and pathologies become more prominent, which negatively impacts the quality of life of an increasing number of individuals.

While several mechanisms and pathways like the WNT, BMP2 or PTH signaling pathway have been thoroughly studied over the last few decades, new scientific capabilities and perspectives allow for a more integrative and comprehensive view on bone development and bone regeneration. With the revolutionary rise of the -omics field and the latest advances in cell lineage tracing models and single cell analysis, new molecular mechanisms are being elucidated and novel important players are being recognized. For example, our understanding of epigenetic processes or metabolites that control bone integrity is growing at a rapid pace. In concert with the progress made recently in the development and design of new scaffolds and biomaterials, all these advances generate novel and alternative approaches to target bone regeneration and are under investigation with the potential to increase the quality of life for many.

This Special Issue of IJMS provides a platform for high-quality publications elucidating novel insights on bone development and/or presenting new molecular and conceptual approaches for the manipulation of osteogenesis and bone regeneration, as well as bone homeostasis. This will generate a representative picture of the latest advances in bone research and serve as a road map for where the bone field is headed.

Dr. Roman Thaler
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • osteoblast
  • osteocyte
  • osteoclast
  • mesenchymal stem cell
  • cell differentiation
  • epigenetics
  • -omics
  • integrative analysis
  • biomaterials

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Published Papers (15 papers)

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Research

Jump to: Review

11 pages, 1369 KiB  
Article
Surface Topography of Titanium Affects Their Osteogenic Potential through DNA Methylation
by Young-Dan Cho, Woo-Jin Kim, Sungtae Kim, Young Ku and Hyun-Mo Ryoo
Int. J. Mol. Sci. 2021, 22(5), 2406; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052406 - 27 Feb 2021
Cited by 12 | Viewed by 2005
Abstract
It is widely accepted that sandblasted/large-grit/acid-etched (SLA) surfaces of titanium (Ti) have a higher osteogenic potential than machined ones. However, most studies focused on differential gene expression without elucidating the underlying mechanism for this difference. The aim of this study was to evaluate [...] Read more.
It is widely accepted that sandblasted/large-grit/acid-etched (SLA) surfaces of titanium (Ti) have a higher osteogenic potential than machined ones. However, most studies focused on differential gene expression without elucidating the underlying mechanism for this difference. The aim of this study was to evaluate how the surface roughness of dental Ti implants affects their osteogenic potential. Mouse preosteoblast MC3T3-E1 cells were seeded on machined and SLA Ti discs. The cellular activities of the discs were analyzed using confocal laser scanning microscopy, proliferation assays, and real-time polymerase chain reaction (PCR). DNA methylation was evaluated using a methylation-specific PCR. The cell morphology was slightly different between the two types of surfaces. While cellular proliferation was slightly greater on the machined surfaces, the osteogenic response of the SLA surfaces was superior, and they showed increased alkaline phosphatase (Alp) activity and higher bone marker gene expression levels (Type I collagen, Alp, and osteocalcin). The degree of DNA methylation on the Alp gene was lower on the SLA surfaces than on the machined surfaces. DNA methyltransferase inhibitor stimulated the Alp gene expression on the machined surfaces, similar to the SLA surfaces. The superior osteogenic potential of the SLA surfaces can be attributed to a different epigenetic landscape, specifically, the DNA methylation of Alp genes. This finding offers novel insights into epigenetics to supplement genetics and raises the possibility of using epidrugs as potential therapeutic targets to enhance osteogenesis on implant surfaces. Full article
(This article belongs to the Special Issue Bone Development and Regeneration)
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14 pages, 37217 KiB  
Article
Intranuclear Delivery of Nuclear Factor-Kappa B p65 in a Rat Model of Tooth Replantation
by Chung-Min Kang, Seunghan Mo, Mijeong Jeon, Ui-Won Jung, Yooseok Shin, Jin-Su Shin, Bo-Young Shin, Sang-Kyou Lee, Hyung-Jun Choi and Je Seon Song
Int. J. Mol. Sci. 2021, 22(4), 1987; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22041987 - 17 Feb 2021
Cited by 2 | Viewed by 2363
Abstract
After avulsion and replantation, teeth are at risk of bone and root resorption. The present study aimed to demonstrate that the intra-nuclear transducible form of transcription modulation domain of p65 (nt-p65-TMD) can suppress osteoclast differentiation in vitro, and reduce bone resorption in a [...] Read more.
After avulsion and replantation, teeth are at risk of bone and root resorption. The present study aimed to demonstrate that the intra-nuclear transducible form of transcription modulation domain of p65 (nt-p65-TMD) can suppress osteoclast differentiation in vitro, and reduce bone resorption in a rat model of tooth replantation. Cell viability and nitric oxide release were evaluated in RAW264.7 cells using CCK-8 assay and Griess reaction kit. Osteoclast differentiation was evaluated using quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and tartrate-resistant acid phosphatase (TRAP) staining. Thirty-two maxillary rat molars were extracted and stored in saline (n = 10) or 10 µM nt-p65-TMD solution (n = 22) before replantation. After 4 weeks, specimens were scored according to the inflammatory pattern using micro-computed tomography (CT) imaging and histological analyses. nt-p65-TMD treatment resulted in significant reduction of nitric oxide release and osteoclast differentiation as studied using PCR and TRAP staining. Further, micro-CT analysis revealed a significant decrease in bone resorption in the nt-p65-TMD treatment group (p < 0.05). Histological analysis of nt-p65-TMD treatment group showed that not only bone and root resorption, but also inflammation of the periodontal ligament and epithelial insertion was significantly reduced. These findings suggest that nt-p65-TMD has the unique capabilities of regulating bone remodeling after tooth replantation. Full article
(This article belongs to the Special Issue Bone Development and Regeneration)
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12 pages, 1720 KiB  
Article
Effects of Estrogen Receptor and Wnt Signaling Activation on Mechanically Induced Bone Formation in a Mouse Model of Postmenopausal Bone Loss
by Astrid Liedert, Claudia Nemitz, Melanie Haffner-Luntzer, Fabian Schick, Franz Jakob and Anita Ignatius
Int. J. Mol. Sci. 2020, 21(21), 8301; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21218301 - 05 Nov 2020
Cited by 16 | Viewed by 2590
Abstract
In the adult skeleton, bone remodeling is required to replace damaged bone and functionally adapt bone mass and structure according to the mechanical requirements. It is regulated by multiple endocrine and paracrine factors, including hormones and growth factors, which interact in a coordinated [...] Read more.
In the adult skeleton, bone remodeling is required to replace damaged bone and functionally adapt bone mass and structure according to the mechanical requirements. It is regulated by multiple endocrine and paracrine factors, including hormones and growth factors, which interact in a coordinated manner. Because the response of bone to mechanical signals is dependent on functional estrogen receptor (ER) and Wnt/β-catenin signaling and is impaired in postmenopausal osteoporosis by estrogen deficiency, it is of paramount importance to elucidate the underlying mechanisms as a basis for the development of new strategies in the treatment of osteoporosis. The present study aimed to investigate the effectiveness of the activation of the ligand-dependent ER and the Wnt/β-catenin signal transduction pathways on mechanically induced bone formation using ovariectomized mice as a model of postmenopausal bone loss. We demonstrated that both pathways interact in the regulation of bone mass adaption in response to mechanical loading and that the activation of Wnt/β-catenin signaling considerably increased mechanically induced bone formation, whereas the effects of estrogen treatment strictly depended on the estrogen status in the mice. Full article
(This article belongs to the Special Issue Bone Development and Regeneration)
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13 pages, 3127 KiB  
Article
Effect of Quercetin 3-O-β-D-Galactopyranoside on the Adipogenic and Osteoblastogenic Differentiation of Human Bone Marrow-Derived Mesenchymal Stromal Cells
by Jung Hwan Oh, Fatih Karadeniz, Youngwan Seo and Chang-Suk Kong
Int. J. Mol. Sci. 2020, 21(21), 8044; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21218044 - 28 Oct 2020
Cited by 16 | Viewed by 2533
Abstract
Natural products, especially phenols, are promising therapeutic agents with beneficial effects against aging-related complications such as osteoporosis. This study aimed to investigate the effect of quercetin 3-O-β-D-galactopyranoside (Q3G), a glycoside of a common bioactive phytochemical quercetin, on osteogenic and adipogenic differentiation [...] Read more.
Natural products, especially phenols, are promising therapeutic agents with beneficial effects against aging-related complications such as osteoporosis. This study aimed to investigate the effect of quercetin 3-O-β-D-galactopyranoside (Q3G), a glycoside of a common bioactive phytochemical quercetin, on osteogenic and adipogenic differentiation of human bone marrow-derived mesenchymal stromal cells (hBM-MSCs). hBM-MSCs were induced to differentiate into osteoblasts and adipocytes in the presence or absence of Q3G and the differentiation markers were analyzed to observe the effect. Q3G treatment stimulated the osteoblastogenesis markers: cell proliferation, alkaline phosphatase (ALP) activity and extracellular mineralization. In addition, it upregulated the expression of RUNX2 and osteocalcin protein as osteoblastogenesis regulating transcription factors. Moreover, Q3G treatment increased the activation of osteoblastogenesis-related Wnt and bone morphogenetic protein (BMP) signaling displayed as elevated levels of phosphorylated β-catenin and Smad1/5 in nuclear fractions of osteo-induced hBM-MSCs. The presence of quercetin in adipo-induced hBM-MSC culture inhibited the adipogenic differentiation depicted as suppressed lipid accumulation and expression of adipogenesis markers such as PPARγ, SREBP1c and C/EBPα. In conclusion, Q3G supplementation stimulated osteoblast differentiation and inhibited adipocyte differentiation in hBM-MSCs via Wnt/BMP and PPARγ pathways, respectively. This study provided useful information of the therapeutic potential of Q3G against osteoporosis mediated via regulation of MSC differentiation. Full article
(This article belongs to the Special Issue Bone Development and Regeneration)
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14 pages, 2352 KiB  
Article
No Role of Osteocytic Osteolysis in the Development and Recovery of the Bone Phenotype Induced by Severe Secondary Hyperparathyroidism in Vitamin D Receptor Deficient Mice
by Barbara M. Misof, Stéphane Blouin, Jochen G. Hofstaetter, Paul Roschger, Jochen Zwerina and Reinhold G. Erben
Int. J. Mol. Sci. 2020, 21(21), 7989; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21217989 - 27 Oct 2020
Cited by 7 | Viewed by 1909
Abstract
Osteocytic osteolysis/perilacunar remodeling is thought to contribute to the maintenance of mineral homeostasis. Here, we utilized a reversible, adult-onset model of secondary hyperparathyroidism to study femoral bone mineralization density distribution (BMDD) and osteocyte lacunae sections (OLS) based on quantitative backscattered electron imaging. Male [...] Read more.
Osteocytic osteolysis/perilacunar remodeling is thought to contribute to the maintenance of mineral homeostasis. Here, we utilized a reversible, adult-onset model of secondary hyperparathyroidism to study femoral bone mineralization density distribution (BMDD) and osteocyte lacunae sections (OLS) based on quantitative backscattered electron imaging. Male mice with a non-functioning vitamin D receptor (VDRΔ/Δ) or wild-type mice were exposed to a rescue diet (RD) (baseline) and subsequently to a low calcium challenge diet (CD). Thereafter, VDRΔ/Δ mice received either the CD, a normal diet (ND), or the RD. At baseline, BMDD and OLS characteristics were similar in VDRΔ/Δ and wild-type mice. The CD induced large cortical pores, osteomalacia, and a reduced epiphyseal average degree of mineralization in the VDRΔ/Δ mice relative to the baseline (−9.5%, p < 0.05 after two months and −10.3%, p < 0.01 after five months of the CD). Switching VDRΔ/Δ mice on the CD back to the RD fully restored BMDD to baseline values. However, OLS remained unchanged in all groups of mice, independent of diet. We conclude that adult VDRΔ/Δ animals on an RD lack any skeletal abnormalities, suggesting that VDR signaling is dispensable for normal bone mineralization as long as mineral homeostasis is normal. Our findings also indicate that VDRΔ/Δ mice attempt to correct a calcium challenge by enhanced osteoclastic resorption rather than by osteocytic osteolysis. Full article
(This article belongs to the Special Issue Bone Development and Regeneration)
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13 pages, 1868 KiB  
Article
18F- based Quantification of the Osteogenic Potential of hMSCs
by Tobias Grossner, Uwe Haberkorn and Tobias Gotterbarm
Int. J. Mol. Sci. 2020, 21(20), 7692; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21207692 - 17 Oct 2020
Cited by 1 | Viewed by 1920
Abstract
In bone tissue engineering, there is a constant need to design new methods for promoting in vitro osteogenic differentiation. Consequently, there is a strong demand for fast, effective and reliable methods to track and quantify osteogenesis in vitro. In this study, we used [...] Read more.
In bone tissue engineering, there is a constant need to design new methods for promoting in vitro osteogenic differentiation. Consequently, there is a strong demand for fast, effective and reliable methods to track and quantify osteogenesis in vitro. In this study, we used the radiopharmacon fluorine-18 (18F) to evaluate the amount of hydroxylapatite produced by mesenchymal stem cells (MSCs) in a monolayer cell culture in vitro. The hydroxylapatite bound tracer was evaluated using µ-positron emission tomography (µ-PET) scanning and activimeter analysis. It was therefore possible to determine the amount of synthesized mineral and thus to conclude the osteogenic potential of the cells. A Student’s t-test revealed a highly significant difference regarding tracer uptake between the osteogenic group and the corresponding control group (µ-PET p = 0.043; activimeter analysis p = 0.012). This tracer uptake showed a highly significant correlation with the gold standard of quantitative Alizarin Red staining (ARS) (r2 = 0.86) as well as with the absolute calcium content detected by inductively coupled plasma mass spectrometry (r2 = 0.81). The results showed that 18F labeling is a novel method to prove and quantify hydroxyapatite content in MSC monolayer cultures. The mineral layer remains intact for further analysis. This non-destructive in vitro method can be used to rapidly investigate bone tissue engineering strategies in terms of hydroxylapatite production, and could therefore accelerate the process of implementing new strategies in clinical practice. Full article
(This article belongs to the Special Issue Bone Development and Regeneration)
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17 pages, 3674 KiB  
Article
Discoidin Domain Receptor 1 Regulates Runx2 during Osteogenesis of Osteoblasts and Promotes Bone Ossification via Phosphorylation of p38
by Liang-Yin Chou, Chung-Hwan Chen, Shu-Chun Chuang, Tsung-Lin Cheng, Yi-Hsiung Lin, Hsin-Chiao Chou, Yin-Chih Fu, Yan-Hsiung Wang and Chau-Zen Wang
Int. J. Mol. Sci. 2020, 21(19), 7210; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197210 - 29 Sep 2020
Cited by 13 | Viewed by 2878
Abstract
Discoidin domain receptor 1 (Drd1) is a collagen-binding membrane protein, but its role in osteoblasts during osteogenesis remains undefined. We generated inducible osteoblast-specific Ddr1 knockout (OKOΔDdr1) mice; their stature at birth, body weight and body length were significantly decreased [...] Read more.
Discoidin domain receptor 1 (Drd1) is a collagen-binding membrane protein, but its role in osteoblasts during osteogenesis remains undefined. We generated inducible osteoblast-specific Ddr1 knockout (OKOΔDdr1) mice; their stature at birth, body weight and body length were significantly decreased compared with those of control Ddr1f/f-4OHT mice. We hypothesize that Ddr1 regulates osteogenesis of osteoblasts. Micro-CT showed that compared to 4-week-old Ddr1f/f-4OHT mice, OKOΔDdr1 mice presented significant decreases in cancellous bone volume and trabecular number and significant increases in trabecular separation. The cortical bone volume was decreased in OKOΔDdr1 mice, resulting in decreased mechanical properties of femurs compared with those of Ddr1f/f-4OHT mice. In femurs of 4-week-old OKOΔDdr1 mice, H&E staining showed fewer osteocytes and decreased cortical bone thickness than Ddr1f/f-4OHT. Osteoblast differentiation markers, including BMP2, Runx2, alkaline phosphatase (ALP), Col-I and OC, were decreased compared with those of control mice. Ddr1 knockdown in osteoblasts resulted in decreased mineralization, ALP activity, phosphorylated p38 and protein levels of BMP2, Runx2, ALP, Col-I and OC during osteogenesis. Overexpression and knockdown of Ddr1 in osteoblasts demonstrated that DDR1 mediates the expression and activity of Runx2 and the downstream osteogenesis markers during osteogenesis through regulation of p38 phosphorylation. Full article
(This article belongs to the Special Issue Bone Development and Regeneration)
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13 pages, 2043 KiB  
Article
Alternating Electric Fields Modify the Function of Human Osteoblasts Growing on and in the Surroundings of Titanium Electrodes
by Franziska Sahm, Josefin Ziebart, Anika Jonitz-Heincke, Doris Hansmann, Thomas Dauben and Rainer Bader
Int. J. Mol. Sci. 2020, 21(18), 6944; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186944 - 22 Sep 2020
Cited by 19 | Viewed by 2862
Abstract
Endogenous electric fields created in bone tissue as a response to mechanical loading are known to influence the activity and differentiation of bone and precursor cells. Thus, electrical stimulation offers an adjunct therapy option for the promotion of bone regeneration. Understanding the influence [...] Read more.
Endogenous electric fields created in bone tissue as a response to mechanical loading are known to influence the activity and differentiation of bone and precursor cells. Thus, electrical stimulation offers an adjunct therapy option for the promotion of bone regeneration. Understanding the influence of electric fields on bone cell function and the identification of suitable electrical stimulation parameters are crucial for the clinical success of stimulation therapy. Therefore, we investigated the impact of alternating electric fields on human osteoblasts that were seeded on titanium electrodes, which delivered the electrical stimulation. Moreover, osteoblasts were seeded on collagen-coated coverslips near the electrodes, representing the bone stock surrounding the implant. Next, 0.2 V, 1.4 V, or 2.8 V were applied to the in vitro system with 20 Hz frequency. After one, three, and seven days, the osteoblast morphology and expression of osteogenic genes were analysed. The actin organisation, as well as the proliferation, were not affected by the electrical stimulation. Changes in the gene expression and protein accumulation after electrical stimulation were voltage-dependent. After three days, the osteogenic gene expression and alkaline phosphatase activity were up to 2.35-fold higher following the electrical stimulation with 0.2 V and 1.4 V on electrodes and coverslips compared to controls. Furthermore, collagen type I mRNA, as well as the amount of the C-terminal propeptide of collagen type I were increased after the stimulation with 0.2 V and 1.4 V, while the higher electrical stimulation with 2.8 V led to decreased levels, especially on the electrodes. Full article
(This article belongs to the Special Issue Bone Development and Regeneration)
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12 pages, 6985 KiB  
Article
3D-Printed Ceramic Bone Scaffolds with Variable Pore Architectures
by Ho-Kyung Lim, Seok-Jin Hong, Sun-Ju Byeon, Sung-Min Chung, Sung-Woon On, Byoung-Eun Yang, Jong-Ho Lee and Soo-Hwan Byun
Int. J. Mol. Sci. 2020, 21(18), 6942; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186942 - 22 Sep 2020
Cited by 43 | Viewed by 4168
Abstract
This study evaluated the mechanical properties and bone regeneration ability of 3D-printed pure hydroxyapatite (HA)/tricalcium phosphate (TCP) pure ceramic scaffolds with variable pore architectures. A digital light processing (DLP) 3D printer was used to construct block-type scaffolds containing only HA and TCP after [...] Read more.
This study evaluated the mechanical properties and bone regeneration ability of 3D-printed pure hydroxyapatite (HA)/tricalcium phosphate (TCP) pure ceramic scaffolds with variable pore architectures. A digital light processing (DLP) 3D printer was used to construct block-type scaffolds containing only HA and TCP after the polymer binder was completely removed by heat treatment. The compressive strength and porosity of the blocks with various structures were measured; scaffolds with different pore sizes were implanted in rabbit calvarial models. The animals were observed for eight weeks, and six animals were euthanized in the fourth and eighth weeks. Then, the specimens were evaluated using radiological and histological analyses. Larger scaffold pore sizes resulted in enhanced bone formation after four weeks (p < 0.05). However, in the eighth week, a correlation between pore size and bone formation was not observed (p > 0.05). The findings showed that various pore architectures of HA/TCP scaffolds can be achieved using DLP 3D printing, which can be a valuable tool for optimizing bone-scaffold properties for specific clinical treatments. As the pore size only influenced bone regeneration in the initial stage, further studies are required for pore-size optimization to balance the initial bone regeneration and mechanical strength of the scaffold. Full article
(This article belongs to the Special Issue Bone Development and Regeneration)
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16 pages, 2983 KiB  
Article
Umbilical Cord Mesenchymal Stem Cell-Derived Nanovesicles Potentiate the Bone-Formation Efficacy of Bone Morphogenetic Protein 2
by Songhyun Lim, Hao-Zhen Lyu, Ju-Ro Lee, Shi Huan Han, Jae Hyup Lee and Byung-Soo Kim
Int. J. Mol. Sci. 2020, 21(17), 6425; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21176425 - 03 Sep 2020
Cited by 8 | Viewed by 3018
Abstract
Recombinant human bone morphogenetic protein 2 (rhBMP-2) is one of the most potent osteogenic factors used to treat bone loss. However, at higher doses, rhBMP-2 does not necessarily increase bone formation but rather increases the incidence of adverse side effects. Here, we investigated [...] Read more.
Recombinant human bone morphogenetic protein 2 (rhBMP-2) is one of the most potent osteogenic factors used to treat bone loss. However, at higher doses, rhBMP-2 does not necessarily increase bone formation but rather increases the incidence of adverse side effects. Here, we investigated whether umbilical cord mesenchymal stem cell (UCMSC)-derived nanovesicles (NVs) further increase the in vivo bone formation at high doses of rhBMP-2. In the presence of UCMSC-derived NVs, proliferation, migration, and tube formation of human umbilical vein endothelial cells were stimulated in vitro. Furthermore, migration and osteogenesis of human bone marrow-derived mesenchymal stem cells were stimulated. To examine the efficacy of UCMSC-derived NVs on in vivo bone formation, collagen sponges soaked with rhBMP-2 and UCMSC-derived NVs were used in athymic nude mice with calvarial defects. At a high rhBMP-2 dosage (500 ng/mL), UCMSC-derived NVs significantly promoted bone formation in calvarial defects; however, the UCMSC-derived NVs alone did not induce in vivo bone formation. Our results indicate that UCMSC-derived NVs can potentiate the bone formation efficacy of rhBMP-2 at a high dosage. Full article
(This article belongs to the Special Issue Bone Development and Regeneration)
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13 pages, 3901 KiB  
Article
Bone Regeneration Capability of 3D Printed Ceramic Scaffolds
by Ju-Won Kim, Byoung-Eun Yang, Seok-Jin Hong, Hyo-Geun Choi, Sun-Ju Byeon, Ho-Kyung Lim, Sung-Min Chung, Jong-Ho Lee and Soo-Hwan Byun
Int. J. Mol. Sci. 2020, 21(14), 4837; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21144837 - 08 Jul 2020
Cited by 48 | Viewed by 4264
Abstract
In this study, we evaluated the bone regenerative capability of a customizable hydroxyapatite (HA) and tricalcium phosphate (TCP) scaffold using a digital light processing (DLP)-type 3D printing system. Twelve healthy adult male beagle dogs were the study subjects. A total of 48 defects [...] Read more.
In this study, we evaluated the bone regenerative capability of a customizable hydroxyapatite (HA) and tricalcium phosphate (TCP) scaffold using a digital light processing (DLP)-type 3D printing system. Twelve healthy adult male beagle dogs were the study subjects. A total of 48 defects were created, with two defects on each side of the mandible in all the dogs. The defect sites in the negative control group (sixteen defects) were left untreated (the NS group), whereas those in the positive control group (sixteen defects) were filled with a particle-type substitute (the PS group). The defect sites in the experimental groups (sixteen defects) were filled with a 3D printed substitute (the 3DS group). Six dogs each were exterminated after healing periods of 4 and 8 weeks. Radiological and histomorphometrical evaluations were then performed. None of the groups showed any specific problems. In radiological evaluation, there was a significant difference in the amount of new bone formation after 4 weeks (p < 0.05) between the PS and 3DS groups. For both of the evaluations, the difference in the total amount of bone after 8 weeks was statistically significant (p < 0.05). There was no statistically significant difference in new bone between the PS and 3DS groups in both evaluations after 8 weeks (p > 0.05). The proposed HA/TCP scaffold without polymers, obtained using the DLP-type 3D printing system, can be applied for bone regeneration. The 3D printing of a HA/TCP scaffold without polymers can be used for fabricating customized bone grafting substitutes. Full article
(This article belongs to the Special Issue Bone Development and Regeneration)
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15 pages, 11216 KiB  
Article
Innate Biomineralization
by Erming Tian, Fumiya Watanabe, Betty Martin and Maurizio Zangari
Int. J. Mol. Sci. 2020, 21(14), 4820; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21144820 - 08 Jul 2020
Cited by 4 | Viewed by 2928
Abstract
In vertebrates, biomineralization is a feature considered unique to mature osteoblasts and odontoblasts by which they synthesize hydroxyapatite (HAP), which is deposited in the collagen matrix to construct endoskeleton. For many decades, the mechanisms that modulate differentiation and maturation of these specialized cells [...] Read more.
In vertebrates, biomineralization is a feature considered unique to mature osteoblasts and odontoblasts by which they synthesize hydroxyapatite (HAP), which is deposited in the collagen matrix to construct endoskeleton. For many decades, the mechanisms that modulate differentiation and maturation of these specialized cells have been sought as a key to understanding bone-remodeling defects. Here, we report that biomineralization is an innate ability of all mammalian cells, irrespective of cell type or maturation stage. This innate biomineralization is triggered by the concomitant exposure of living cells to three indispensable elements: calcium ion, phosphoester salt, and alkaline phosphatase. Any given somatic cell, including undifferentiated mononuclear cells, can undergo a biomineralization process to produce calcium-phosphate agglomerates. The biologically generated minerals under such conditions are composed of genuine HAP crystallites of Ca10(PO4)6(OH)2 and 5–10 nanometer (nm) in size. This discovery will profoundly improve our understanding of bone metabolism and ectopic calcifications. Full article
(This article belongs to the Special Issue Bone Development and Regeneration)
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Review

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18 pages, 2445 KiB  
Review
Relevance of Notch Signaling for Bone Metabolism and Regeneration
by Tobias M. Ballhause, Shan Jiang, Anke Baranowsky, Sabine Brandt, Peter R. Mertens, Karl-Heinz Frosch, Timur Yorgan and Johannes Keller
Int. J. Mol. Sci. 2021, 22(3), 1325; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22031325 - 29 Jan 2021
Cited by 40 | Viewed by 5252
Abstract
Notch1-4 receptors and their signaling pathways are expressed in almost all organ systems and play a pivotal role in cell fate decision by coordinating cell proliferation, differentiation and apoptosis. Differential expression and activation of Notch signaling pathways has been observed in a variety [...] Read more.
Notch1-4 receptors and their signaling pathways are expressed in almost all organ systems and play a pivotal role in cell fate decision by coordinating cell proliferation, differentiation and apoptosis. Differential expression and activation of Notch signaling pathways has been observed in a variety of organs and tissues under physiological and pathological conditions. Bone tissue represents a dynamic system, which is constantly remodeled throughout life. In bone, Notch receptors have been shown to control remodeling and regeneration. Numerous functions have been assigned to Notch receptors and ligands, including osteoblast differentiation and matrix mineralization, osteoclast recruitment and cell fusion and osteoblast/osteoclast progenitor cell proliferation. The expression and function of Notch1-4 in the skeleton are distinct and closely depend on the temporal expression at different differentiation stages. This review addresses the current knowledge on Notch signaling in adult bone with emphasis on metabolism, bone regeneration and degenerative skeletal disorders, as well as congenital disorders associated with mutant Notch genes. Moreover, the crosstalk between Notch signaling and other important pathways involved in bone turnover, including Wnt/β-catenin, BMP and RANKL/OPG, are outlined. Full article
(This article belongs to the Special Issue Bone Development and Regeneration)
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33 pages, 5430 KiB  
Review
Advances in Growth Factor Delivery for Bone Tissue Engineering
by Érica Resende Oliveira, Lei Nie, Daria Podstawczyk, Ahmad Allahbakhsh, Jithendra Ratnayake, Dandara Lima Brasil and Amin Shavandi
Int. J. Mol. Sci. 2021, 22(2), 903; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22020903 - 18 Jan 2021
Cited by 95 | Viewed by 7656
Abstract
Shortcomings related to the treatment of bone diseases and consequent tissue regeneration such as transplants have been addressed to some extent by tissue engineering and regenerative medicine. Tissue engineering has promoted structures that can simulate the extracellular matrix and are capable of guiding [...] Read more.
Shortcomings related to the treatment of bone diseases and consequent tissue regeneration such as transplants have been addressed to some extent by tissue engineering and regenerative medicine. Tissue engineering has promoted structures that can simulate the extracellular matrix and are capable of guiding natural bone repair using signaling molecules to promote osteoinduction and angiogenesis essential in the formation of new bone tissues. Although recent studies on developing novel growth factor delivery systems for bone repair have attracted great attention, taking into account the complexity of the extracellular matrix, scaffolding and growth factors should not be explored independently. Consequently, systems that combine both concepts have great potential to promote the effectiveness of bone regeneration methods. In this review, recent developments in bone regeneration that simultaneously consider scaffolding and growth factors are covered in detail. The main emphasis in this overview is on delivery strategies that employ polymer-based scaffolds for spatiotemporal-controlled delivery of both single and multiple growth factors in bone-regeneration approaches. From clinical applications to creating alternative structural materials, bone tissue engineering has been advancing constantly, and it is relevant to regularly update related topics. Full article
(This article belongs to the Special Issue Bone Development and Regeneration)
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Review
Transcriptional Regulation of Dental Epithelial Cell Fate
by Keigo Yoshizaki, Satoshi Fukumoto, Daniel D. Bikle and Yuko Oda
Int. J. Mol. Sci. 2020, 21(23), 8952; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21238952 - 25 Nov 2020
Cited by 12 | Viewed by 3771
Abstract
Dental enamel is hardest tissue in the body and is produced by dental epithelial cells residing in the tooth. Their cell fates are tightly controlled by transcriptional programs that are facilitated by fate determining transcription factors and chromatin regulators. Understanding the transcriptional program [...] Read more.
Dental enamel is hardest tissue in the body and is produced by dental epithelial cells residing in the tooth. Their cell fates are tightly controlled by transcriptional programs that are facilitated by fate determining transcription factors and chromatin regulators. Understanding the transcriptional program controlling dental cell fate is critical for our efforts to build and repair teeth. In this review, we describe the current understanding of these regulators essential for regeneration of dental epithelial stem cells and progeny, which are identified through transgenic mouse models. We first describe the development and morphogenesis of mouse dental epithelium in which different subpopulations of epithelia such as ameloblasts contribute to enamel formation. Then, we describe the function of critical factors in stem cells or progeny to drive enamel lineages. We also show that gene mutations of these factors are associated with dental anomalies in craniofacial diseases in humans. We also describe the function of the master regulators to govern dental lineages, in which the genetic removal of each factor switches dental cell fate to that generating hair. The distinct and related mechanisms responsible for the lineage plasticity are discussed. This knowledge will lead us to develop a potential tool for bioengineering new teeth. Full article
(This article belongs to the Special Issue Bone Development and Regeneration)
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