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12 pages, 3423 KiB

Open AccessArticle

CaSR-Mediated hBMSCs Activity Modulation: Additional Coupling Mechanism in Bone Remodeling Compartment

by Hyunji Cho, Jisoo Lee, Seoyoung Jang, Jungsun Lee, Tong In Oh, Youngsook Son and EunAh Lee

Int. J. Mol. Sci. 2021, 22(1), 325; https://doi.org/10.3390/ijms22010325 - 30 Dec 2020

Cited by 6 | Viewed by 2048

Abstract

Near the bone remodeling compartments (BRC), extracellular calcium concentration (Ca²⁺_o) is locally elevated and bone marrow stromal cells (BMSCs) close to the BRC can be exposed to high calcium concentration. The calcium-sensing receptor (CaSR) is known to play a key [...] Read more.

Near the bone remodeling compartments (BRC), extracellular calcium concentration (Ca²⁺_o) is locally elevated and bone marrow stromal cells (BMSCs) close to the BRC can be exposed to high calcium concentration. The calcium-sensing receptor (CaSR) is known to play a key role in maintaining extracellular calcium homeostasis by sensing fluctuations in the levels of extracellular calcium (Ca²⁺_o). When human BMSCs (hBMSCs) were exposed to various calcium concentrations (1.8, 3, 5, 10, 30 mM), moderate-high extracellular calcium concentrations (3–5 mM) stimulated proliferation, while a high calcium concentration (30 mM) inhibited the proliferation. Exposure to various calcium concentrations did not induce significant differences in the apoptotic cell fraction. Evaluation of multi-lineage differentiation potential showed no significant difference among various calcium concentration groups, except for the high calcium concentration (30 mM) treated group, which resulted in increased calcification after in vitro osteogenic differentiation. Treatment of NPS2143, a CaSR inhibitor, abolished the stimulatory effect on hBMSCs proliferation and migration indicating that CaSR is involved. These results suggest that the calcium concentration gradient near the BRC may play an important role in bone remodeling by acting as an osteoblast–osteoclast coupling mechanism through CaSR. Full article

(This article belongs to the Special Issue Novel Extracellular and Intracellular Signalling Mechanisms in Bone)

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14 pages, 5440 KiB

Open AccessArticle

Spatio-Temporal Bone Remodeling after Hematopoietic Stem Cell Transplantation

by Constanze S. Schwarz, Christian H. Bucher, Claudia Schlundt, Sarah Mertlitz, Katarina Riesner, Martina Kalupa, Lydia Verlaat, Oskar Schmidt-Bleek, Radost A. Sass, Katharina Schmidt-Bleek, Georg N. Duda, Olaf Penack and Il-Kang Na

Int. J. Mol. Sci. 2021, 22(1), 267; https://doi.org/10.3390/ijms22010267 - 29 Dec 2020

Cited by 2 | Viewed by 2860

Abstract

The interaction of hematopoietic cells and the bone microenvironment to maintain bone homeostasis is increasingly appreciated. We hypothesized that the transfer of allogeneic T lymphocytes has extensive effects on bone biology and investigated trabecular and cortical bone structures, the osteoblast reconstitution, and the [...] Read more.

The interaction of hematopoietic cells and the bone microenvironment to maintain bone homeostasis is increasingly appreciated. We hypothesized that the transfer of allogeneic T lymphocytes has extensive effects on bone biology and investigated trabecular and cortical bone structures, the osteoblast reconstitution, and the bone vasculature in experimental hematopoietic stem cell transplantations (HSCT). Allogeneic or syngeneic hematopoietic stem cells (HSC) and allogeneic T lymphocytes were isolated and transferred in a murine model. After 20, 40, and 60 days, bone structures were visualized using microCT and histology. Immune cells were monitored using flow cytometry and bone vessels, bone cells and immune cells were fluorescently stained and visualized. Remodeling of the bone substance, the bone vasculature and bone cell subsets were found to occur as early as day +20 after allogeneic HSCT (including allogeneic T lymphocytes) but not after syngeneic HSCT. We discovered that allogeneic HSCT (including allogeneic T lymphocytes) results in a transient increase of trabecular bone number and bone vessel density. This was paralleled by a cortical thinning as well as disruptive osteoblast lining and loss of B lymphocytes. In summary, our data demonstrate that the adoptive transfer of allogeneic HSCs and allogeneic T lymphocytes can induce profound structural and spatial changes of bone tissue homeostasis as well as bone marrow cell composition, underlining the importance of the adaptive immune system for maintaining a balanced bone biology. Full article

(This article belongs to the Special Issue Novel Extracellular and Intracellular Signalling Mechanisms in Bone)

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16 pages, 1530 KiB

Open AccessArticle

Effects of PIN on Osteoblast Differentiation and Matrix Mineralization through Runt-Related Transcription Factor

by Kyung-Ran Park, SooHyun Kim, MyoungLae Cho, Sang Wook Kang and Hyung-Mun Yun

Int. J. Mol. Sci. 2020, 21(24), 9579; https://doi.org/10.3390/ijms21249579 - 16 Dec 2020

Cited by 14 | Viewed by 2622

Abstract

Styrax Japonica Sieb. et Zucc. has been used as traditional medicine in inflammatory diseases, and isolated compounds have shown pharmacological activities. Pinoresinol glucoside (PIN) belonging to lignins was isolated from the stem bark of S. Japonica. This study aimed to investigate the biological [...] Read more.

Styrax Japonica Sieb. et Zucc. has been used as traditional medicine in inflammatory diseases, and isolated compounds have shown pharmacological activities. Pinoresinol glucoside (PIN) belonging to lignins was isolated from the stem bark of S. Japonica. This study aimed to investigate the biological function and mechanisms of PIN on cell migration, osteoblast differentiation, and matrix mineralization. Herein, we investigated the effects of PIN in MC3T3-E1 pre-osteoblasts, which are widely used for studying osteoblast behavior in in vitro cell systems. At concentrations ranging from 0.1 to 100 μM, PIN had no cell toxicity in pre-osteoblasts. Pre-osteoblasts induced osteoblast differentiation, and the treatment of PIN (10 and 30 μM) promoted the cell migration rate in a dose-dependent manner. At concentrations of 10 and 30 μM, PIN elevated early osteoblast differentiation in a dose-dependent manner, as indicated by increases in alkaline phosphatase (ALP) staining and activity. Subsequently, PIN also increased the formation of mineralized nodules in a dose-dependent manner, as indicated by alizarin red S (ARS) staining, demonstrating positive effects of PIN on late osteoblast differentiation. In addition, PIN induced the mRNA level of BMP2, ALP, and osteocalcin (OCN). PIN also upregulated the protein level of BMP2 and increased canonical BMP2 signaling molecules, the phosphorylation of Smad1/5/8, and the protein level of Runt-related transcription factor 2 (RUNX2). Furthermore, PIN activated non-canonical BMP2 signaling molecules, activated MAP kinases, and increased β-catenin signaling. The findings of this study indicate that PIN has biological roles in osteoblast differentiation and matrix mineralization, and suggest that PIN might have anabolic effects in bone diseases such as osteoporosis and periodontitis. Full article

(This article belongs to the Special Issue Novel Extracellular and Intracellular Signalling Mechanisms in Bone)

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15 pages, 2781 KiB

Open AccessArticle

7-HYB, a Phenolic Compound Isolated from Myristica fragrans Houtt Increases Cell Migration, Osteoblast Differentiation, and Mineralization through BMP2 and β-catenin Signaling

by Kyung-Ran Park, Yoon-Ju Kwon, Ji-Eun Park and Hyung-Mun Yun

Int. J. Mol. Sci. 2020, 21(21), 8059; https://doi.org/10.3390/ijms21218059 - 29 Oct 2020

Cited by 7 | Viewed by 2546

Abstract

The seeds (nutmegs) of Myristica fragrans Houtt have been used as popular spices and traditional medicine to treat a variety of diseases. A phenolic compound, ((7S)-8′-(benzo[3′,4′]dioxol-1′-yl)-7-hydroxypropyl)benzene-2,4-diol (7-HYB) was isolated from the seeds of M. fragrans. This study aimed to investigate the anabolic [...] Read more.

The seeds (nutmegs) of Myristica fragrans Houtt have been used as popular spices and traditional medicine to treat a variety of diseases. A phenolic compound, ((7S)-8′-(benzo[3′,4′]dioxol-1′-yl)-7-hydroxypropyl)benzene-2,4-diol (7-HYB) was isolated from the seeds of M. fragrans. This study aimed to investigate the anabolic effects of 7-HYB in osteogenesis and bone mineralization. In the present study, 7-HYB promotes the early and late differentiation of MC3T3-E1 preosteoblasts. 7-HYB also elevated cell migration rate during differentiation of the preosteoblasts with the increased phosphorylation of mitogen-activated protein kinases (MAPKs) including ERK1/2, p38, and JNK. In addition, 7-HYB induced the protein level of BMP2, the phosphorylation of Smad1/5/8, and the expression of RUNX2. 7-HYB also inhibited GSK3β and subsequently increased the level of β-catenin. However, in bone marrow macrophages (BMMs), 7-HYB has no biological effects in cell viability, TRAP-positive multinuclear osteoclasts, and gene expression (c-Fos and NF-ATc1) in receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis. Our findings suggest that 7-HYB plays an important role in osteoblast differentiation through the BMP2 and β-catenin signaling pathway. It also indicates that 7-HYB might have a therapeutic effect for the treatment of bone diseases such as osteoporosis and periodontitis. Full article

(This article belongs to the Special Issue Novel Extracellular and Intracellular Signalling Mechanisms in Bone)

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11 pages, 4206 KiB

Open AccessArticle

A Novel Role of Interleukin-6 as a Regulatory Factor of Inflammation-Associated Deterioration in Osteoblast Arrangement

by Aira Matsugaki, Shun Matsumoto and Takayoshi Nakano

Int. J. Mol. Sci. 2020, 21(18), 6659; https://doi.org/10.3390/ijms21186659 - 11 Sep 2020

Cited by 9 | Viewed by 3897

Abstract

Inflammatory disorders are associated with bone destruction; that is, deterioration in bone cell activities are under the control of the innate immune system. Macrophages play a central role in innate immunity by switching their polarized phenotype. A disturbed immune system causes aberrance in [...] Read more.

Inflammatory disorders are associated with bone destruction; that is, deterioration in bone cell activities are under the control of the innate immune system. Macrophages play a central role in innate immunity by switching their polarized phenotype. A disturbed immune system causes aberrance in the ordered bone matrix microarrangement, which is a dominant determinant of bone tissue functionalization. However, the precise relationship between the immune system and bone tissue organization is unknown. In this study, the controlled in vitro co-culture assay results showed that M1-polarized macrophages disrupted the osteoblast alignment, which directly modulate the oriented bone matrix organization, by secreting pro-inflammatory cytokines. Notably, interleukin-6 was found to be a key regulator of unidirectional osteoblast alignment. Our results demonstrated that inflammatory diseases triggered bone dysfunction by regulating the molecular interaction between the immune system and bone tissue organization. These findings may contribute to the development of therapeutic targets for inflammatory disorders, including rheumatoid arthritis. Full article

(This article belongs to the Special Issue Novel Extracellular and Intracellular Signalling Mechanisms in Bone)

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14 pages, 2940 KiB

Open AccessArticle

A Phytochemical Constituent, (E)-Methyl-Cinnamate Isolated from Alpinia katsumadai Hayata Suppresses Cell Survival, Migration, and Differentiation in Pre-Osteoblasts

by Kyung-Ran Park, Hanna Lee, MyoungLae Cho and Hyung-Mun Yun

Int. J. Mol. Sci. 2020, 21(10), 3700; https://doi.org/10.3390/ijms21103700 - 24 May 2020

Cited by 18 | Viewed by 3569

Abstract

Background: (E)-methyl-cinnamate (EMC), a phytochemical constituent isolated from Alpinia katsumadai Hayata, is a natural flavor compound with anti-inflammatory properties, which is widely used in the food and commodity industry. However, the pharmacological effects of methyl-cinnamate on pre-osteoblasts remain unknown. This study aimed to [...] Read more.

Background: (E)-methyl-cinnamate (EMC), a phytochemical constituent isolated from Alpinia katsumadai Hayata, is a natural flavor compound with anti-inflammatory properties, which is widely used in the food and commodity industry. However, the pharmacological effects of methyl-cinnamate on pre-osteoblasts remain unknown. This study aimed to investigate the pharmacological effects and mechanisms of EMC in pre-osteoblast MC3T3-E1 cells (pre-osteoblasts). Methods: Cell viability and apoptosis were evaluated using the MTT assay and TUNEL staining. Cell migration and osteoblast differentiation were examined using migration assays, as well as alkaline phosphatase activity and staining assays. Western blot analysis was used to examine intracellular signaling pathways and apoptotic proteins. Results: EMC decreased cell viability with morphological changes and increased apoptosis in pre-osteoblasts. EMC also induced the cleavage of Poly (ADP-ribose) polymerase (PARP) and caspase-3 and reduced the expression of anti-apoptotic proteins. In addition, EMC increased TUNEL-positive cells in pre-osteoblasts, decreased the activation of mitogen-activated protein kinases, and suppressed cell migration rate in pre-osteoblasts. Subsequently, EMC inhibited the osteoblast differentiation of pre-osteoblasts, as assessed by alkaline phosphatase staining and activity assays. Conclusion: These findings demonstrate that EMC has a pharmacological and biological role in cell survival, migration, and osteoblast differentiation. It suggests that EMC might be a potential phytomedicine for treating abnormalities of osteoblast function in bone diseases. Full article

(This article belongs to the Special Issue Novel Extracellular and Intracellular Signalling Mechanisms in Bone)

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24 pages, 5517 KiB

Open AccessArticle

Dysbacteriosis-Derived Lipopolysaccharide Causes Embryonic Osteopenia through Retinoic-Acid-Regulated DLX5 Expression

by Lingsen You, Liwei Zhu, Pei-zhi Li, Guang Wang, Hongmei Cai, Jinhuan Song, Denglu Long, Zachary Berman, Li Lin, Xin Cheng and Xuesong Yang

Int. J. Mol. Sci. 2020, 21(7), 2518; https://doi.org/10.3390/ijms21072518 - 4 Apr 2020

Cited by 4 | Viewed by 3488

Abstract

Growing evidence suggests an adverse impact of gut microbiota dysbiosis on human health. However, it remains unclear whether embryonic osteogenesis is affected by maternal gut dysbacteriosis. In this study, we observed that elevated lipopolysaccharide (LPS) levels led to skeletal developmental retardation in an [...] Read more.

Growing evidence suggests an adverse impact of gut microbiota dysbiosis on human health. However, it remains unclear whether embryonic osteogenesis is affected by maternal gut dysbacteriosis. In this study, we observed that elevated lipopolysaccharide (LPS) levels led to skeletal developmental retardation in an established mouse model of gut microbiota dysbiosis. Using chick embryos exposed to dysbacteriosis-derived LPS, we found restriction in the development of long bones as demonstrated by Alcian blue and alizarin red staining. Micro-CT and histological analysis exhibited decreased trabecular volume, bone mineral density, and collagen production, as well as suppressed osteoblastic gene expression (Ocn, Runx2, Osx, and Dlx5) in chick embryonic phalanges following LPS treatment. Atomic force microscopy manifested decreased roughness of MC3T3-E1 cells and poorly developed matrix vesicles (MVs) in presence of LPS. The expression of the aforementioned osteoblastic genes was suppressed in MC3T3-E1 cells as well. High-throughput RNA sequencing indicated that retinoic acid (RA) may play an important role in LPS-induced osteopenia. The addition of RA suppressed Dlx5 expression in MC3T3-E1 cells, as was also seen when exposed to LPS. Quantitative PCR, Western blot, and immunofluorescent staining showed that retinoic acid receptor α (RARα) was upregulated by LPS or RA treatment, while the expression of DLX5 was downregulated. CYP1B1 expression was increased by LPS treatment in MC3T3-E1 cells, which might be attributed to the increased inflammatory factors and subsequently activated NF-κB signaling. Eventually, blocking RA signals with AGN193109 successfully restored LPS-inhibited osteoblastic gene expression. Taken together, our data reveals that maternal gut microbiota dysbiosis can interfere with bone ossification, in which Dlx5 expression regulated by RA signaling plays an important role. Full article

(This article belongs to the Special Issue Novel Extracellular and Intracellular Signalling Mechanisms in Bone)

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22 pages, 36912 KiB

Open AccessArticle

Hyperbaric Oxygen Therapy Improves the Osteogenic and Vasculogenic Properties of Mesenchymal Stem Cells in the Presence of Inflammation In Vitro

by Chiara Gardin, Gerardo Bosco, Letizia Ferroni, Silvia Quartesan, Alex Rizzato, Marco Tatullo and Barbara Zavan

Int. J. Mol. Sci. 2020, 21(4), 1452; https://doi.org/10.3390/ijms21041452 - 20 Feb 2020

Cited by 47 | Viewed by 5911

Abstract

Hyperbaric oxygen (HBO) therapy has been reported to be beneficial for treating many conditions of inflammation-associated bone loss. The aim of this work was to in vitro investigate the effect of HBO in the course of osteogenesis of human Mesenchymal Stem Cells (MSCs) [...] Read more.

Hyperbaric oxygen (HBO) therapy has been reported to be beneficial for treating many conditions of inflammation-associated bone loss. The aim of this work was to in vitro investigate the effect of HBO in the course of osteogenesis of human Mesenchymal Stem Cells (MSCs) grown in a simulated pro-inflammatory environment. Cells were cultured with osteogenic differentiation factors in the presence or not of the pro-inflammatory cytokine Tumor Necrosis Factor-α (TNF-α), and simultaneously exposed daily for 60 min, and up to 21 days, at 2,4 atmosphere absolute (ATA) and 100% O₂. To elucidate osteogenic differentiation-dependent effects, cells were additionally pre-committed prior to treatments. Cell metabolic activity was evaluated by means of the MTT assay and DNA content quantification, whereas osteogenic and vasculogenic differentiation was assessed by quantification of extracellular calcium deposition and gene expression analysis. Metabolic activity and osteogenic properties of cells did not differ between HBO, high pressure (HB) alone, or high oxygen (HO) alone and control if cells were pre-differentiated to the osteogenic lineage. In contrast, when treatments started contextually to the osteogenic differentiation of the cells, a significant reduction in cell metabolic activity first, and in mineral deposition at later time points, were observed in the HBO-treated group. Interestingly, TNF-α supplementation determined a significant improvement in the osteogenic capacity of cells subjected to HBO, which was not observed in TNF-α-treated cells exposed to HB or HO alone. This study suggests that exposure of osteogenic-differentiating MSCs to HBO under in vitro simulated inflammatory conditions enhances differentiation towards the osteogenic phenotype, providing evidence of the potential application of HBO in all those processes requiring bone regeneration. Full article

(This article belongs to the Special Issue Novel Extracellular and Intracellular Signalling Mechanisms in Bone)

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Review

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21 pages, 2035 KiB

Open AccessReview

MicroRNAs Modulate Signaling Pathways in Osteogenic Differentiation of Mesenchymal Stem Cells

by Chiara Mazziotta, Carmen Lanzillotti, Maria Rosa Iaquinta, Francesca Taraballi, Elena Torreggiani, John Charles Rotondo, Lucia Otòn-Gonzalez, Elisa Mazzoni, Francesca Frontini, Ilaria Bononi, Monica De Mattei, Mauro Tognon and Fernanda Martini

Int. J. Mol. Sci. 2021, 22(5), 2362; https://doi.org/10.3390/ijms22052362 - 27 Feb 2021

Cited by 38 | Viewed by 5545

Abstract

Mesenchymal stem cells (MSCs) have been identified in many adult tissues and they have been closely studied in recent years, especially in view of their potential use for treating diseases and damaged tissues and organs. MSCs are capable of self-replication and differentiation into [...] Read more.

Mesenchymal stem cells (MSCs) have been identified in many adult tissues and they have been closely studied in recent years, especially in view of their potential use for treating diseases and damaged tissues and organs. MSCs are capable of self-replication and differentiation into osteoblasts and are considered an important source of cells in tissue engineering for bone regeneration. Several epigenetic factors are believed to play a role in the osteogenic differentiation of MSCs, including microRNAs (miRNAs). MiRNAs are small, single-stranded, non-coding RNAs of approximately 22 nucleotides that are able to regulate cell proliferation, differentiation and apoptosis by binding the 3′ untranslated region (3′-UTR) of target mRNAs, which can be subsequently degraded or translationally silenced. MiRNAs control gene expression in osteogenic differentiation by regulating two crucial signaling cascades in osteogenesis: the transforming growth factor-beta (TGF-β)/bone morphogenic protein (BMP) and the Wingless/Int-1(Wnt)/β-catenin signaling pathways. This review provides an overview of the miRNAs involved in osteogenic differentiation and how these miRNAs could regulate the expression of target genes. Full article

(This article belongs to the Special Issue Novel Extracellular and Intracellular Signalling Mechanisms in Bone)

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17 pages, 1047 KiB

Open AccessReview

Biomineralization of Collagen-Based Materials for Hard Tissue Repair

by Le Yu and Mei Wei

Int. J. Mol. Sci. 2021, 22(2), 944; https://doi.org/10.3390/ijms22020944 - 19 Jan 2021

Cited by 80 | Viewed by 8902

Abstract

Hydroxyapatite (HA) reinforced collagen fibrils serve as the basic building blocks of natural bone and dentin. Mineralization of collagen fibrils play an essential role in ensuring the structural and mechanical functionalities of hard tissues such as bone and dentin. Biomineralization of collagen can [...] Read more.

Hydroxyapatite (HA) reinforced collagen fibrils serve as the basic building blocks of natural bone and dentin. Mineralization of collagen fibrils play an essential role in ensuring the structural and mechanical functionalities of hard tissues such as bone and dentin. Biomineralization of collagen can be divided into intrafibrillar and extrafibrillar mineralization in terms of HA distribution relative to collagen fibrils. Intrafibrillar mineralization is termed when HA minerals are incorporated within the gap zone of collagen fibrils, while extrafibrillar mineralization refers to the minerals that are formed on the surface of collagen fibrils. However, the mechanisms resulting in these two types of mineralization still remain debatable. In this review, the evolution of both classical and non-classical biomineralization theories is summarized. Different intrafibrillar mineralization mechanisms, including polymer induced liquid precursor (PILP), capillary action, electrostatic attraction, size exclusion, Gibbs-Donnan equilibrium, and interfacial energy guided theories, are discussed. Exemplary strategies to induce biomimetic intrafibrillar mineralization using non-collagenous proteins (NCPs), polymer analogs, small molecules, and fluidic shear stress are discussed, and recent applications of mineralized collagen fibers for bone regeneration and dentin repair are included. Finally, conclusions are drawn on these proposed mechanisms, and the future trend of collagen-based materials for bone regeneration and tooth repair is speculated. Full article

(This article belongs to the Special Issue Novel Extracellular and Intracellular Signalling Mechanisms in Bone)

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23 pages, 1970 KiB

Open AccessReview

The Role of MicroRNAs in Bone Metabolism and Disease

by Yongguang Gao, Suryaji Patil and Airong Qian

Int. J. Mol. Sci. 2020, 21(17), 6081; https://doi.org/10.3390/ijms21176081 - 24 Aug 2020

Cited by 45 | Viewed by 5056

Abstract

Bone metabolism is an intricate process involving various bone cells, signaling pathways, cytokines, hormones, growth factors, etc., and the slightest deviation can result in various bone disorders including osteoporosis, arthropathy, and avascular necrosis of femoral head. Osteoporosis is one of the most prevalent [...] Read more.

Bone metabolism is an intricate process involving various bone cells, signaling pathways, cytokines, hormones, growth factors, etc., and the slightest deviation can result in various bone disorders including osteoporosis, arthropathy, and avascular necrosis of femoral head. Osteoporosis is one of the most prevalent disorders affecting the skeleton, which is characterized by low bone mass and bone mineral density caused by the disruption in the balanced process of bone formation and bone resorption. The current pharmaceutical treatments such as bisphosphonates, selective estrogen receptor modulator, calcitonin, teriparatide, etc., could decrease the risk of fractures but have side-effects that have limited their long term applications. MicroRNAs (miRNAs) are one of many non-coding RNAs. These are single-stranded with a length of 19–25 nucleotides and can influence various cellular processes and play an important role in various diseases. Therefore, in this article, we review the different functions of different miRNA in bone metabolism and osteoporosis to understand their mechanism of action for the development of possible therapeutics. Full article

(This article belongs to the Special Issue Novel Extracellular and Intracellular Signalling Mechanisms in Bone)

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