Editorial

4 pages, 212 KiB

Open AccessEditorial

by Kazuo Yudoh, Yodo Sugishita and Yuki Suzuki-Takahashi

Int. J. Mol. Sci. 2023, 24(10), 8761; https://doi.org/10.3390/ijms24108761 - 15 May 2023

Cited by 3 | Viewed by 1102

Bone is an important tissue which is a structural body component, carrying out the roles of mechanical stress response and organ/tissue protection [...] Full article

(This article belongs to the Special Issue Bone Development and Regeneration 3.0)

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16 pages, 10142 KiB

Open AccessArticle

The Effect of Low-Intensity Pulsed Ultrasound on Bone Regeneration and the Expression of Osterix and Cyclooxygenase-2 during Critical-Size Bone Defect Repair

by Darian Volarić, Gordana Žauhar, Jie Chen, Ana Terezija Jerbić Radetić, Hrvoje Omrčen, Antonio Raič, Roko Pirović and Olga Cvijanović Peloza

Int. J. Mol. Sci. 2024, 25(7), 3882; https://doi.org/10.3390/ijms25073882 - 30 Mar 2024

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Abstract

Low-intensity pulsed ultrasound (LIPUS) is a form of ultrasound that utilizes low-intensity pulsed waves. Its effect on bones that heal by intramembranous ossification has not been sufficiently investigated. In this study, we examined LIPUS and the autologous bone, to determine their effect on [...] Read more.

Low-intensity pulsed ultrasound (LIPUS) is a form of ultrasound that utilizes low-intensity pulsed waves. Its effect on bones that heal by intramembranous ossification has not been sufficiently investigated. In this study, we examined LIPUS and the autologous bone, to determine their effect on the healing of the critical-size bone defect (CSBD) of the rat calvaria. The bone samples underwent histological, histomorphometric and immunohistochemical analyses. Both LIPUS and autologous bone promoted osteogenesis, leading to almost complete closure of the bone defect. On day 30, the bone volume was the highest in the autologous bone group (20.35%), followed by the LIPUS group (19.12%), and the lowest value was in the control group (5.11%). The autologous bone group exhibited the highest intensities of COX-2 (167.7 ± 1.1) and Osx (177.1 ± 0.9) expression on day 30. In the LIPUS group, the highest intensity of COX-2 expression was found on day 7 (169.7 ±1.6) and day 15 (92.7 ± 2.2), while the highest Osx expression was on day 7 (131.9 ± 0.9). In conclusion, this study suggests that LIPUS could represent a viable alternative to autologous bone grafts in repairing bone defects that are ossified by intramembranous ossification. Full article

(This article belongs to the Special Issue Bone Development and Regeneration 3.0)

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20 pages, 5120 KiB

Open AccessArticle

by Jiewen Zhang, Kentaro Akiyama, Aung Ye Mun, Ryuji Tagashira, Tingling Zou, Naoya Matsunaga, Teisaku Kohno and Takuo Kuboki

Int. J. Mol. Sci. 2024, 25(6), 3252; https://doi.org/10.3390/ijms25063252 - 13 Mar 2024

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Abstract

Mesenchymal stem cells (MSCs) are known to promote tissue regeneration and suppress excessive inflammation caused by infection or trauma. Reported evidence indicates that various factors influence the expression of MSCs’ endogenous immunomodulatory properties. However, the detailed interactions of MSCs with macrophages, which are [...] Read more.

Mesenchymal stem cells (MSCs) are known to promote tissue regeneration and suppress excessive inflammation caused by infection or trauma. Reported evidence indicates that various factors influence the expression of MSCs’ endogenous immunomodulatory properties. However, the detailed interactions of MSCs with macrophages, which are key cells involved in tissue repair, and their regulatory mechanisms are not completely understood. We herein investigated how age-related immunomodulatory impairment of MSCs alters the interaction of MSCs with macrophages during bone healing using young (5-week old) and aged (50-week old) mice. To clarify the relationship between inflammatory macrophages (M1) and MSCs, their spatiotemporal localization at the bone healing site was investigated by immunostaining, and possible regulatory mechanisms were analyzed in vitro co-cultures. Histomorphometric analysis revealed an accumulation of M1 and a decrease in MSC number at the healing site in aged mice, which showed a delayed bone healing. In in vitro co-cultures, MSCs induced M1 apoptosis through cell-to-cell contact but suppressed the gene expression of pro-inflammatory cytokines by soluble factors secreted in the culture supernatant. Interestingly, interleukin 38 (Il-38) expression was up-regulated in M1 after co-culture with MSCs. IL-38 suppressed the gene expression of inflammatory cytokines in M1 and promoted the expression of genes associated with M1 polarization to anti-inflammatory macrophages (M2). IL-38 also had an inhibitory effect on M1 apoptosis. These results suggest that MSCs may induce M1 apoptosis, suppress inflammatory cytokine production by M1, and induce their polarization toward M2. Nevertheless, in aged conditions, the decreased number and immunomodulatory function of MSCs could be associated with a delayed M1 clearance (i.e., apoptosis and/or polarization) and consequent delayed resolution of the inflammatory phase. Furthermore, M1-derived IL-38 may be associated with immunoregulation in the tissue regeneration site. Full article

(This article belongs to the Special Issue Bone Development and Regeneration 3.0)

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21 pages, 18046 KiB

Open AccessArticle

TMEM119 (c.G143A, p.S48L) Mutation Is Involved in Primary Failure of Eruption by Attenuating Glycolysis-Mediated Osteogenesis

by Mindi Xu, Dandan Wang, Kefan Li, Tianyu Ma, Yixiang Wang and Bin Xia

Int. J. Mol. Sci. 2024, 25(5), 2821; https://doi.org/10.3390/ijms25052821 - 29 Feb 2024

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Abstract

Primary failure of eruption (PFE) is a rare oral disease with an incidence rate of 0.06%. It is characterized by abnormal eruption mechanisms that disrupt tooth eruption. The underlying pathogenic genetic variant and mechanism of PFE remain largely unknown. The purpose of this [...] Read more.

Primary failure of eruption (PFE) is a rare oral disease with an incidence rate of 0.06%. It is characterized by abnormal eruption mechanisms that disrupt tooth eruption. The underlying pathogenic genetic variant and mechanism of PFE remain largely unknown. The purpose of this study was to explore the role of a novel transmembrane protein 119 (TMEM119) mutation in two PFE patients in a Chinese family. Information collection was performed on the family with a diagnosis of PFE, and blood samples from patients and healthy family members were extracted. Whole-exome sequencing was performed. Bioinformatics analysis revealed that a heterozygous variant in the TMEM119 gene (c.G143A, p.S48L) was a disease-associated mutation in this family. Recombinant pcDNA3.1 plasmid-containing wild-type and mutant TMEM119 expression cassettes were successfully constructed and transfected into MC3T3-E1 cells, respectively. The results of in vitro analysis suggested that the subcellular distribution of the TMEM119 protein was transferred from the cell cytoplasm to the nucleus, and the ability of cells to proliferate and migrate as well as glycolytic and mineralized capacities were reduced after mutation. Furthermore, rescue assays showed that activating transcription factor 4 (ATF4) overexpression rescued the attenuated glycolysis and mineralization ability of cells. Results of in vivo analysis demonstrated that TMEM119 was mainly expressed in the alveolar bone around the mouse molar germs, and the expression level increased with tooth eruption, demonstrated using immunohistochemistry and immunofluorescence. Collectively, the novel TMEM119 mutation is potentially pathogenic in the PFE family by affecting the glucose metabolism and mineralized function of osteoblasts, including interaction with ATF4. Our findings broaden the gene mutation spectrum of PFE and further elucidate the pathogenic mechanism of PFE. Full article

(This article belongs to the Special Issue Bone Development and Regeneration 3.0)

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18 pages, 5299 KiB

Open AccessArticle

Lipopolysaccharide Impedes Bone Repair in FcγRIIB-Deficient Mice

by Sirikanda Jantaboon, Nithidol Sakunrangsit, Parichart Toejing, Asada Leelahavanichkul, Prapaporn Pisitkun, Matthew B. Greenblatt and Sutada Lotinun

Int. J. Mol. Sci. 2023, 24(23), 16944; https://doi.org/10.3390/ijms242316944 - 29 Nov 2023

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Abstract

Chronic inflammation contributes to the development of skeletal disorders in patients with systemic lupus erythematosus (SLE). Activation of the host immune response stimulates osteoclast activity, which in turn leads to bone loss. Regenerating bone in the inflammatory microenvironments of SLE patients with critical [...] Read more.

Chronic inflammation contributes to the development of skeletal disorders in patients with systemic lupus erythematosus (SLE). Activation of the host immune response stimulates osteoclast activity, which in turn leads to bone loss. Regenerating bone in the inflammatory microenvironments of SLE patients with critical bone defects remains a great challenge. In this study, we utilized lipopolysaccharide (LPS) to imitate locally and systemically pathogenic bacterial infection and examined the bone regeneration performance of LPS-associated mandibular and tibial bone regeneration impairment in FcγRIIB^−/− mice. Our results indicated that a loss of FcγRIIB alleviates bone regeneration in both mandibles and tibiae. After LPS induction, FcγRIIB^−/− mice were susceptible to impaired fracture healing in tibial and mandibular bones. LPS decreased the mineralization to collagen ratio in FcγRIIB^−/− mice, indicating a mineralization defect during bone repair. An osteoblast-associated gene (Col1a1) was attenuated in FcγRIIB-deficient mice, whereas Bglap, Hhip, and Creb5 were further downregulated with LPS treatment in FcγRIIB^−/− mice compared to FcγRIIB^−/− mice. Alpl and Bglap expression was dcreased in osteoblasts derived from bone chips. An osteoclast-associated gene, Tnfsf11/Tnfrsf11 ratio, ewas increased in LPS-induced FcγRIIB^−/− mice and in vitro. Furthermore, systemic LPS was relatively potent in stimulating production of pro-inflammatory cytokines including TNF-α, IL-6, and MCP-1 in FcγRIIB^−/− mice compared to FcγRIIB^−/− mice. The levels of TNF-α, IFN-β, IL-1α, and IL-17A were increased, whereas IL-10 and IL-23 were decreased in FcγRIIB^−/− mice treated locally with LPS. These findings suggest that both local and systemic LPS burden can exacerbate bone regeneration impairment, delay mineralization and skeletal repair, and induce inflammation in SLE patients. Full article

(This article belongs to the Special Issue Bone Development and Regeneration 3.0)

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15 pages, 3956 KiB

Open AccessArticle

Exosomes Derived from Adipose Stem Cells Enhance Bone Fracture Healing via the Activation of the Wnt3a/β-Catenin Signaling Pathway in Rats with Type 2 Diabetes Mellitus

by Dong Zhang, Weidong Xiao, Changjiang Liu, Zheng Wang, Yuhang Liu, Yifeng Yu, Chao Jian and Aixi Yu

Int. J. Mol. Sci. 2023, 24(5), 4852; https://doi.org/10.3390/ijms24054852 - 02 Mar 2023

Cited by 9 | Viewed by 1690

Abstract

Nonunion and delayed union are common complications of diabetes mellitus that pose a serious health threat to people. There are many approaches that have been used to improve bone fracture healing. Recently, exosomes have been regarded as promising medical biomaterials for improving fracture [...] Read more.

Nonunion and delayed union are common complications of diabetes mellitus that pose a serious health threat to people. There are many approaches that have been used to improve bone fracture healing. Recently, exosomes have been regarded as promising medical biomaterials for improving fracture healing. However, whether exosomes derived from adipose stem cells can promote bone fracture healing in diabetes mellitus remains unclear. In this study, adipose stem cells (ASCs) and exosomes derived from adipose stem cells (ASCs-exos) are isolated and identified. Additionally, we evaluate the in vitro and in vivo effects of ASCs-exos on the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) and bone repair and the regeneration in a rat model of nonunion via Western blotting, immunofluorescence assay, ALP staining, alizarin red staining, radiographic examination and histological analysis. Compared with controls, ASCs-exos promoted BMSC osteogenic differentiation. Additionally, the results of Western blotting, radiographic examination and histological analysis show that ASCs-exos improve the ability for fracture repair in the rat model of nonunion bone fracture healing. Moreover, our results further proved that ASCs-exos play a role in activating the Wnt3a/β-catenin signaling pathway, which facilitates the osteogenic differentiation of BMSCs. All these results show that ASCs-exos enhance the osteogenic potential of BMSCs by activating the Wnt/β-catenin signaling pathway, and also facilitate the ability for bone repair and regeneration in vivo, which provides a novel direction for fracture nonunion in diabetes mellitus treatment. Full article

(This article belongs to the Special Issue Bone Development and Regeneration 3.0)

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18 pages, 6663 KiB

Open AccessArticle

Atf7ip Inhibits Osteoblast Differentiation via Negative Regulation of the Sp7 Transcription Factor

by Guoqin Hu, Xian Shi, Xiuxia Qu, Chunqing Han, Anran Hu, Zhongtang Jia, Jiatao Yang, Huanliang Liu and Yu Wu

Int. J. Mol. Sci. 2023, 24(5), 4305; https://doi.org/10.3390/ijms24054305 - 21 Feb 2023

Cited by 1 | Viewed by 1727

Abstract

Epigenetic modifications are critical for cell differentiation and growth. As a regulator of H3K9 methylation, Setdb1 is implicated in osteoblast proliferation and differentiation. The activity and nucleus localization of Setdb1 are regulated by its binding partner, Atf7ip. However, whether Atf7ip is involved in [...] Read more.

Epigenetic modifications are critical for cell differentiation and growth. As a regulator of H3K9 methylation, Setdb1 is implicated in osteoblast proliferation and differentiation. The activity and nucleus localization of Setdb1 are regulated by its binding partner, Atf7ip. However, whether Atf7ip is involved in the regulation of osteoblast differentiation remains largely unclear. In the present study, we found that Atf7ip expression was upregulated during the osteogenesis of primary bone marrow stromal cells and MC3T3-E1 cells, and was induced in PTH-treated cells. The overexpression of Atf7ip impaired osteoblast differentiation in MC3T3-E1 cells regardless of PTH treatment, as measured by the expression of osteoblast differentiation markers, Alp-positive cells, Alp activity, and calcium deposition. Conversely, the depletion of Atf7ip in MC3T3-E1 cells promoted osteoblast differentiation. Compared with the control mice, animals with Atf7ip deletion in the osteoblasts (Oc-Cre;Atf7ip^f/f) showed more bone formation and a significant increase in the bone trabeculae microarchitecture, as reflected by μ-CT and bone histomorphometry. Mechanistically, Atf7ip contributed to the nucleus localization of Setdb1 in MC3T3-E1, but did not affect Setdb1 expression. Atf7ip negatively regulated Sp7 expression, and through specific siRNA, Sp7 knockdown attenuated the enhancing role of Atf7ip deletion in osteoblast differentiation. Through these data, we identified Atf7ip as a novel negative regulator of osteogenesis, possibly via its epigenetic regulation of Sp7 expression, and demonstrated that Atf7ip inhibition is a potential therapeutic measure for enhancing bone formation. Full article

(This article belongs to the Special Issue Bone Development and Regeneration 3.0)

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16 pages, 5819 KiB

Open AccessArticle

^99mTc-HDP Labeling—A Non-Destructive Method for Real-Time Surveillance of the Osteogenic Differentiation Potential of hMSC during Ongoing Cell Cultures

by Jakob Hofmann, Kai Borcherding, Karsten Thiel, Thomas Lingner, Ulrike Sommer, Uwe Haberkorn, Tim Niklas Bewersdorf, Gerhard Schmidmaier and Tobias Grossner

Int. J. Mol. Sci. 2022, 23(24), 15874; https://doi.org/10.3390/ijms232415874 - 14 Dec 2022

Cited by 3 | Viewed by 1160

Abstract

99-Metastabil Technetium (^99mTc) is a radiopharmaceutical widely used in skeletal scintigraphy. Recent publications show it can also be used to determine the osteogenic potential of human mesenchymal stem cells (hMSCs) by binding to hydroxyapatite formed during bone tissue engineering. This field [...] Read more.

99-Metastabil Technetium (^99mTc) is a radiopharmaceutical widely used in skeletal scintigraphy. Recent publications show it can also be used to determine the osteogenic potential of human mesenchymal stem cells (hMSCs) by binding to hydroxyapatite formed during bone tissue engineering. This field lacks non-destructive methods to track live osteogenic differentiation of hMSCs. However, no data about the uptake kinetics of ^99mTc and its effect on osteogenesis of hMSCs have been published yet. We therefore evaluated the saturation time of ^99mTc by incubating hMSC cultures for different periods, and the saturation concentration by using different amounts of ^99mTc activity for incubation. The influence of ^99mTc on osteogenic potential of hMSCs was then evaluated by labeling a continuous hMSC culture three times over the course of 3 weeks, and comparing the findings to cultures labeled once. Our findings show that ^99mTc saturation time is less than 0.25 h, and saturation concentration is between 750 and 1000 MBq. Repeated exposure to γ-radiation emitted by ^99mTc had no negative effects on hMSC cultures. These new insights can be used to make this highly promising method broadly available to support researchers in the field of bone tissue engineering using this method to track and evaluate, in real-time, the osteogenic differentiation of hMSC, without any negative influence on the cell viability, or their osteogenic differentiation potential. Full article

(This article belongs to the Special Issue Bone Development and Regeneration 3.0)

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