Scleraxis upregulated by transforming growth factor-β1 signaling inhibits tension-induced osteoblast differentiation of priodontal ligament cells via ephrin A2

Kawatsu, Masayoshi; Takeshita, Nobuo; Takimoto, Atsushi; Yoshimoto, Yuki; Seiryu, Masahiro; Ito, Arata; Kimura, Seiji; Kawamoto, Tadafumi; Hiraki, Yuji; Shukunami, Chisa; Takano‐Yamamoto, Teruko

doi:10.1016/j.bone.2021.115969

Cited by 12 publications

(7 citation statements)

References 41 publications

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“…Several mechanisms are known to contribute to osteoblastic differentiation . Prior studies suggested that M2 macrophage polarization may contribute to osteoblastic differentiation and bone mineralization. , Macrophages have two subphenotypes, and the polarization state of macrophages is dependent on factors in the microenvironment, including several cytokines and chemokines .…”

Section: Resultsmentioning

confidence: 99%

“…In addition, to study the impact of M2 macrophage polarization on extracellular matrix mineralization, MSCs in the lower chamber were continuously cultured for 7 or 21 days and then assessed with alkaline phosphatase (ALP) or Alizarin Red Several mechanisms are known to contribute to osteoblastic differentiation. 35 Prior studies suggested that M2 macrophage polarization may contribute to osteoblastic differentiation and bone mineralization. 36,37 Macrophages have two subphenotypes, and the polarization state of macrophages is dependent on factors in the microenvironment, including several cytokines and chemokines.…”

Section: M2 Macrophage Polarization Induces Mscs Toward Osteoblastic ...mentioning

confidence: 99%

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Dual-Targeted Nanoplatform Regulating the Bone Immune Microenvironment Enhances Fracture Healing

Zhou

Lin

Xiong

et al. 2021

ACS Appl. Mater. Interfaces

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The immune system and skeletal system are closely linked. Macrophages are one of the most important immune cells for bone remodeling, playing a prohealing role mainly through M2 phenotype polarization. Baicalein (5,6,7-trihydroxyflavone, BCL) has been well documented to have a noticeable promotion effect on M2 macrophage polarization. However, due to the limitations in targeted delivery to macrophages and the toxic effect on other organs, BCL has rarely been used in the treatment of bone fractures. In this study, we developed mesoporous silica and Fe3O4 composite-targeted nanoparticles loaded with BCL (BCL@MMSNPs-SS-CD-NW), which could be magnetically delivered to the fracture site. This induced macrophage recruitment in a targeted manner, polarizing them toward the M2 phenotype, which was demonstrated to induce mesenchymal stem cells (MSCs) toward osteoblastic differentiation. The mesoporous silicon nanoparticles (MSNs) were prepared with surface sulfhydrylation and amination modification, and the mesoporous channels were blocked with β-cyclodextrin. The outer layer of the mesoporous silicon was added with an amantane-modified NW-targeting peptide to obtain the targeted nanosystem. After entering macrophages, BCL could be released from nanoparticles since the disulfide linker could be cleaved by intracellular glutathione (GSH), resulting in the removal of cyclodextrin (CD) gatekeeper, which is a key element in the pro-bone-remodeling functions such as anti-inflammation and induction of M2 macrophage polarization to facilitate osteogenic differentiation. This nanosystem passively accumulated in the fracture site, promoting osteogenic differentiation activities, highlighting a potent therapeutic benefit with high biosafety.

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Section: Resultsmentioning

confidence: 99%

Section: M2 Macrophage Polarization Induces Mscs Toward Osteoblastic ...mentioning

confidence: 99%

Dual-Targeted Nanoplatform Regulating the Bone Immune Microenvironment Enhances Fracture Healing

Zhou

Lin

Xiong

et al. 2021

ACS Appl. Mater. Interfaces

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“… 19 Tensile force upregulated scleraxis, inhibiting ossification in PDLCs through TGF-β-ephrin A2 signaling. 39 In human gingival fibroblasts, compressive force increased cell proliferation, ECM synthesis and TGF-β expression, and a TGF-β inhibitor attenuated these effects. 25 In this study, ICF significantly induced mRNA and protein expression of Tgfb1 in iPSCs.…”

Section: Discussionmentioning

confidence: 99%

Intermittent compressive force induces cell cycling and reduces apoptosis in embryoid bodies of mouse induced pluripotent stem cells

et al. 2022

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In vitro manipulation of induced pluripotent stem cells (iPSCs) by environmental factors is of great interest for three-dimensional (3D) tissue/organ induction. The effects of mechanical force depend on many factors, including force and cell type. However, information on such effects in iPSCs is lacking. The aim of this study was to identify a molecular mechanism in iPSCs responding to intermittent compressive force (ICF) by analyzing the global gene expression profile. Embryoid bodies of mouse iPSCs, attached on a tissue culture plate in 3D form, were subjected to ICF in serum-free culture medium for 24 h. Gene ontology analyses for RNA sequencing data demonstrated that genes differentially regulated by ICF were mainly associated with metabolic processes, membrane and protein binding. Topology-based analysis demonstrated that ICF induced genes in cell cycle categories and downregulated genes associated with metabolic processes. The Kyoto Encyclopedia of Genes and Genomes database revealed differentially regulated genes related to the p53 signaling pathway and cell cycle. qPCR analysis demonstrated significant upregulation of Ccnd1, Cdk6 and Ccng1. Flow cytometry showed that ICF induced cell cycle and proliferation, while reducing the number of apoptotic cells. ICF also upregulated transforming growth factor β1 (Tgfb1) at both mRNA and protein levels, and pretreatment with a TGF-β inhibitor (SB431542) prior to ICF abolished ICF-induced Ccnd1 and Cdk6 expression. Taken together, these findings show that TGF-β signaling in iPSCs enhances proliferation and decreases apoptosis in response to ICF, that could give rise to an efficient protocol to manipulate iPSCs for organoid fabrication.

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“…The present study suggests that the expression of the Mkx gene may not be involved in the osteogenic differentiation of HPLFs or in the suppression of osteogenic differentiation ( Figure 6 A). The Scx gene has been reported to be involved in the inhibition of osteogenesis in the periodontal ligament [ 11 , 62 ] and is thought to be important in maintaining the width of the periodontal ligament. In the present study, we found that the expression of the Scx gene was increased when HPLFs were cultured in (+/+) medium compared to other media ( Figure 6 B).…”

Section: Discussionmentioning

confidence: 99%

Wnt/β-Catenin Signaling Inhibits Osteogenic Differentiation in Human Periodontal Ligament Fibroblasts

Iizumi

Honda

2022

Biomimetics

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The periodontal ligament is a collagenous tissue that is important for maintaining the homeostasis of cementum and alveolar bone. In tendon cells, Wnt/β-catenin signaling has been reported to regulate the expression level of Scleraxis (Scx) and Mohawk Homeobox (Mkx) gene and maintain the tissue homeostasis, while its role in the periodontal ligament is unclear. The aim of this study was to investigate the effects of Wnt/β-catenin signaling induced by Wnt-3a stimulation on the inhibition of osteogenic differentiation of human periodontal ligament fibroblasts (HPLFs). During osteogenic differentiation of HPLFs, they formed bone nodules independently of alkaline phosphatase (ALP) activity. After stimulation of Wnt-3a, the expression of β-catenin increased, and nuclear translocation of β-catenin was observed. These data indicate that Wnt-3a activated Wnt/β-catenin signaling. Furthermore, the stimulation of Wnt-3a inhibited the bone nodule formation and suppressed the expression of osteogenic differentiation-related genes such as Runx2, Osteopontin and Osteocalcin, and upregulated the gene expression of Type-I collagen and Periostin (Postn). Scx may be involved in the suppression of osteogenic differentiation in HPLFs. In conclusion, Wnt/β-catenin signaling may be an important signaling pathway that inhibits the osteogenic differentiation in HPLFs by the upregulation of Scx gene expression and downregulation of osteogenic differentiation-related genes.

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Scleraxis upregulated by transforming growth factor-β1 signaling inhibits tension-induced osteoblast differentiation of priodontal ligament cells via ephrin A2

Cited by 12 publications

References 41 publications

Dual-Targeted Nanoplatform Regulating the Bone Immune Microenvironment Enhances Fracture Healing

Dual-Targeted Nanoplatform Regulating the Bone Immune Microenvironment Enhances Fracture Healing

Intermittent compressive force induces cell cycling and reduces apoptosis in embryoid bodies of mouse induced pluripotent stem cells

Wnt/β-Catenin Signaling Inhibits Osteogenic Differentiation in Human Periodontal Ligament Fibroblasts

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