The Experts below are selected from a list of 69975 Experts worldwide ranked by ideXlab platform
Toshihisa Komori - One of the best experts on this subject based on the ideXlab platform.
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Roles of Runx2 in Skeletal Development.
Advances in Experimental Medicine and Biology, 2017Co-Authors: Toshihisa KomoriAbstract:Runx2 is the most upstream transcription factor essential for osteoblast differentiation. It regulates the expression of Sp7, the protein of which is a crucial transcription factor for osteoblast differentiation, as well as that of bone matrix genes including Spp1, Ibsp, and Bglap2. Runx2 is also required for chondrocyte maturation, and Runx3 has a redundant function with Runx2 in chondrocyte maturation. Runx2 regulates the expression of Col10a1, Spp1, Ibsp, and Mmp13 in chondrocytes. It also inhibits chondrocytes from acquiring the phenotypes of permanent cartilage chondrocytes. It regulates chondrocyte proliferation through the regulation of Ihh expression. Runx2 enhances osteoclastogenesis by regulating Rankl. Cbfb, which is a co-transcription factor for Runx family proteins, plays an important role in Skeletal Development by stabilizing Runx family proteins. In Cbfb isoforms, Cbfb1 is more potent than Cbfb2 in Runx2-dependent transcriptional regulation; however, the expression level of Cbfb2 is three-fold higher than that of Cbfb1, demonstrating the requirement of Cbfb2 in Skeletal Development. The expression of Runx2 in osteoblasts is regulated by a 343-bp enhancer located upstream of the P1 promoter. This enhancer is activated by an enhanceosome composed of Dlx5/6, Mef2, Tcf7, Ctnnb1, Sox5/6, Smad1, and Sp7. Thus, Runx2 is a multifunctional transcription factor that is essential for Skeletal Development, and Cbfb regulates Skeletal Development by modulating the stability and transcriptional activity of Runx family proteins.
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Cbfb2 Isoform Dominates More Potent Cbfb1 and Is Required for Skeletal Development
Journal of Bone and Mineral Research, 2016Co-Authors: Qing Jiang, Hisato Komori, Xin Qin, Tetsuya Kawane, Yuki Matsuo, Ichiro Taniuchi, Kosei Ito, Shin-ichi Izumi, Toshihisa KomoriAbstract:Cbfb is a cotranscription factor that forms a heterodimer with Runx proteins Runx1, Runx2, and Runx3. It is required for fetal liver hematopoiesis and Skeletal Development. Cbfb has two functional isoforms, Cbfb1 and Cbfb2, which are formed by alternative splicing. To address the biological functions of these isoforms in Skeletal Development, we examined Cbfb1(-/-) and Cbfb2(-/-) mouse embryos. Intramembranous and endochondral ossification was retarded and chondrocyte and osteoblast differentiation was inhibited in Cbfb2(-/-) embryos but not in Cbfb1(-/-) embryos. Cbfb2 mRNA was upregulated in calvariae, limbs, livers, thymuses, and hearts of Cbfb1(-/-) embryos but Cbfb1 mRNA was not in those of Cbfb2(-/-) embryos, and the total amount of Cbfb1 and Cbfb2 mRNA in Cbfb1(-/-) embryos was similar to that in wild-type embryos but was severely reduced in Cbfb2(-/-) embryos. The absolute numbers of Cbfb2 mRNA in calvariae, limbs, livers, thymuses, and brains in wild-type embryos were about three times higher than those of Cbfb1 in the respective tissue. The levels of Runx proteins were reduced in calvariae, limbs, and primary osteoblasts from Cbfb2(-/-) embryos, but the reduction in Runx2 protein was very mild. Furthermore, the amounts of Runx proteins and Cbfb in Cbfb2(-/-) embryos differed similarly among Skeletal tissues, livers, and thymuses, suggesting that Runx proteins and Cbfb are mutually required for their stability. Although Cbfb1(-/-) embryos developed normally, Cbfb1 induced chondrocyte and osteoblast differentiation and enhanced DNA binding of Runx2 more efficiently than Cbfb2. Our results indicate that modulations in the relative levels of the isoforms may adjust transcriptional activation by Runx2 to appropriate physiological levels. Cbfb2 was more abundant, but Cbfb1 was more potent for enhancing Runx2 activity. Although only Cbfb2 loss generated overt Skeletal phenotypes, both may play major roles in Skeletal Development with functional redundancy. © 2016 American Society for Bone and Mineral Research.
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Akt regulates Skeletal Development through GSK3, mTOR, and FoxOs.
Developmental Biology, 2009Co-Authors: Satoshi Rokutanda, Naoko Kanatani, Carolina A Yoshida, Takashi Fujita, Hisato Komori, Wenguang Liu, Akio Mizuno, Toshihisa KomoriAbstract:Abstract Although Akt plays key roles in various cellular processes, the functions of Akt and Akt downstream signaling pathways in the cellular processes of Skeletal Development remain to be clarified. By analyzing transgenic embryos that expressed constitutively active Akt (myrAkt) or dominant-negative Akt in chondrocytes, we found that Akt positively regulated the four processes of chondrocyte maturation, chondrocyte proliferation, cartilage matrix production, and cell growth in Skeletal Development. As phosphorylation of GSK3β, S6K, and FoxO3a was enhanced in the growth plates of myrAkt transgenic mice, we examined the Akt downstream signaling pathways by organ culture. The Akt-mTOR pathway was responsible for positive regulation of the four cellular processes. The Akt-FoxO pathway enhanced chondrocyte proliferation but inhibited chondrocyte maturation and cartilage matrix production, while the Akt-GSK3 pathway negatively regulated three of the cellular processes in limb skeletons but not in vertebrae due to less GSK3 expression in vertebrae. These findings indicate that Akt positively regulates the cellular processes of Skeletal growth and endochondral ossification, that the Akt-mTOR, Akt-FoxO, and Akt-GSK3 pathways positively or negatively regulate the cellular processes, and that Akt exerts its function in Skeletal Development by tuning the three pathways in a manner dependent on the Skeletal part.
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Requisite roles of Runx2 and Cbfb in Skeletal Development.
Journal of bone and mineral metabolism, 2003Co-Authors: Toshihisa KomoriAbstract:Each Runx (runt-related gene) protein exerts a fundamental role in different cell lineages. Runx2 is essential for osteoblast differentiation and plays an important role in chondrocyte maturation. Runx2 determines the lineage of osteoblastic cells from multipotent mesenchymal cells, enhances osteoblast differentiation at an early stage, and inhibits osteoblast differentiation at a late stage. In addition, Runx2 is involved in the production of bone matrix proteins. Further, Runx2 is a positive regulator of chondrocyte maturation and is involved in vascular invasion into the cartilage. Core binding factor β (Cbfb) is a cotranscription factor which forms a heterodimer with Runx proteins. Cbfb is required for the functions of Runx1 and Runx2. Thus, Runx2/Cbfb heterodimers play essential roles in Skeletal Development.
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core binding factor beta interacts with runx2 and is required for Skeletal Development
Nature Genetics, 2002Co-Authors: Carolina A Yoshida, Masanobu Satake, Tatsuya Furuichi, Naoko Kanatani, Ryo Fukuyama, Takashi Fujita, Kenji Takada, Shinji Kobayashi, Toshihisa KomoriAbstract:Core-binding factor β (CBFβ, also called polyomavirus enhancer binding protein 2β (PEBP2B)) is associated with an inversion of chromosome 16 and is associated with acute myeloid leukemia in humans1. CBFβ forms a heterodimer with RUNX1 (runt-related transcription factor 1), which has a DNA binding domain homologous to the pair-rule protein runt in Drosophila melanogaster. Both RUNX1 and CBFβ are essential for hematopoiesis2,3,4,5,6. Haploinsufficiency of another runt-related protein, RUNX2 (also called CBFA1), causes cleidocranial dysplasia in humans7 and is essential in Skeletal Development by regulating osteoblast differentiation and chondrocyte maturation8,9,10,11,12,13,14,15. Mice deficient in Cbfb (Cbfb−/−) die at midgestation4,5,6, so the function of Cbfβ in Skeletal Development has yet to be ascertained. To investigate this issue, we rescued hematopoiesis of Cbfb−/− mice by introducing Cbfb using the Gata1 promoter. The rescued Cbfb−/− mice recapitulated fetal liver hematopoiesis in erythroid and megakaryocytic lineages and survived until birth, but showed severely delayed bone formation. Although mesenchymal cells differentiated into immature osteoblasts, intramembranous bones were poorly formed. The maturation of chondrocytes into hypertrophic cells was markedly delayed, and no endochondral bones were formed. Electrophoretic mobility shift assays and reporter assays showed that Cbfβ was necessary for the efficient DNA binding of Runx2 and for Runx2-dependent transcriptional activation. These findings indicate that Cbfβ is required for the function of Runx2 in Skeletal Development.
Hideo Morioka - One of the best experts on this subject based on the ideXlab platform.
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The unfolded protein response in Skeletal Development and homeostasis
Cellular and Molecular Life Sciences, 2016Co-Authors: Keisuke Horiuchi, Takahide Tohmonda, Hideo MoriokaAbstract:Osteoblasts and chondrocytes produce a large number of extracellular matrix proteins to generate and maintain the Skeletal system. To cope with their functions as secretory cells, these cells must acquire a considerable capacity for protein synthesis and also the machinery for the quality-control and transport of newly synthesized secreted proteins. The unfolded protein response (UPR) plays a crucial role during the differentiation of these cells to achieve this goal. Unexpectedly, however, studies in the past several years have revealed that the UPR has more extensive functions in Skeletal Development than was initially assumed, and the UPR critically orchestrates many facets of Skeletal Development and homeostasis. This review focuses on recent findings on the functions of the UPR in the differentiation of osteoblasts, chondrocytes, and osteoclasts. These findings may have a substantial impact on our understanding of bone metabolism and also on establishing treatments for congenital and acquired Skeletal disorders.
Shinsuke Ohba - One of the best experts on this subject based on the ideXlab platform.
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Identification of the gene-regulatory landscape in Skeletal Development and potential links to Skeletal regeneration.
Regenerative Therapy, 2017Co-Authors: Hironori Hojo, Ung-il Chung, Shinsuke OhbaAbstract:A class of gene-regulatory elements called enhancers are the main mediators controlling quantitative, temporal and spatial gene expressions. In the course of evolution, the enhancer landscape of higher organisms such as mammals has become quite complex, exerting biological functions precisely and coordinately. In mammalian Skeletal Development, the master transcription factors Sox9, Runx2 and Sp7/Osterix function primarily through enhancers on the genome to achieve specification and differentiation of Skeletal cells. Recently developed genome-scale analyses have shed light on multiple layers of gene regulations, uncovering not only the primary mode of actions of these transcription factors on Skeletal enhancers, but also the relation of the epigenetic landscape to three-dimensional chromatin architecture. Here, we review findings on the emerging framework of gene-regulatory networks involved in Skeletal Development. We further discuss the power of genome-scale analyses to provide new insights into genetic diseases and regenerative medicine in Skeletal tissues.
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An Emerging Regulatory Landscape for Skeletal Development
Trends in Genetics, 2016Co-Authors: Hironori Hojo, Andrew P. Mcmahon, Shinsuke OhbaAbstract:Skeletal Development creates the physical framework that shapes our body and its actions. In the past two decades, genetic studies have provided important insights into the molecular processes at play, including the roles of signaling pathways and transcriptional effectors that coordinate an orderly, progressive emergence and expansion of distinct cartilage and bone cell fates in an invariant temporal and spatial pattern for any given Skeletal element within that specific vertebrate species. Genome-scale studies have provided additional layers of understanding, moving from individual genes to the gene regulatory landscape, integrating regulatory information through cis-regulatory modules into cell type-specific gene regulatory programs. This review discusses our current understanding of the transcriptional control of mammalian Skeletal Development, focusing on recent genome-scale studies.
Keisuke Horiuchi - One of the best experts on this subject based on the ideXlab platform.
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The unfolded protein response in Skeletal Development and homeostasis
Cellular and Molecular Life Sciences, 2016Co-Authors: Keisuke Horiuchi, Takahide Tohmonda, Hideo MoriokaAbstract:Osteoblasts and chondrocytes produce a large number of extracellular matrix proteins to generate and maintain the Skeletal system. To cope with their functions as secretory cells, these cells must acquire a considerable capacity for protein synthesis and also the machinery for the quality-control and transport of newly synthesized secreted proteins. The unfolded protein response (UPR) plays a crucial role during the differentiation of these cells to achieve this goal. Unexpectedly, however, studies in the past several years have revealed that the UPR has more extensive functions in Skeletal Development than was initially assumed, and the UPR critically orchestrates many facets of Skeletal Development and homeostasis. This review focuses on recent findings on the functions of the UPR in the differentiation of osteoblasts, chondrocytes, and osteoclasts. These findings may have a substantial impact on our understanding of bone metabolism and also on establishing treatments for congenital and acquired Skeletal disorders.
Guiqian Chen - One of the best experts on this subject based on the ideXlab platform.
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tgf β and bmp signaling in osteoblast Skeletal Development and bone formation homeostasis and disease
Bone research, 2016Co-Authors: Guiqian ChenAbstract:Transforming growth factor-beta (TGF-β) and bone morphogenic protein (BMP) signaling has fundamental roles in both embryonic Skeletal Development and postnatal bone homeostasis. TGF-βs and BMPs, acting on a tetrameric receptor complex, transduce signals to both the canonical Smad-dependent signaling pathway (that is, TGF-β/BMP ligands, receptors, and Smads) and the non-canonical-Smad-independent signaling pathway (that is, p38 mitogen-activated protein kinase/p38 MAPK) to regulate mesenchymal stem cell differentiation during Skeletal Development, bone formation and bone homeostasis. Both the Smad and p38 MAPK signaling pathways converge at transcription factors, for example, Runx2 to promote osteoblast differentiation and chondrocyte differentiation from mesenchymal precursor cells. TGF-β and BMP signaling is controlled by multiple factors, including the ubiquitin-proteasome system, epigenetic factors, and microRNA. Dysregulated TGF-β and BMP signaling result in a number of bone disorders in humans. Knockout or mutation of TGF-β and BMP signaling-related genes in mice leads to bone abnormalities of varying severity, which enable a better understanding of TGF-β/BMP signaling in bone and the signaling networks underlying osteoblast differentiation and bone formation. There is also crosstalk between TGF-β/BMP signaling and several critical cytokines' signaling pathways (for example, Wnt, Hedgehog, Notch, PTHrP, and FGF) to coordinate osteogenesis, Skeletal Development, and bone homeostasis. This review summarizes the recent advances in our understanding of TGF-β/BMP signaling in osteoblast differentiation, chondrocyte differentiation, Skeletal Development, cartilage formation, bone formation, bone homeostasis, and related human bone diseases caused by the disruption of TGF-β/BMP signaling.
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tgf β and bmp signaling in osteoblast Skeletal Development and bone formation homeostasis and disease
Bone research, 2016Co-Authors: Mengrui Wu, Guiqian Chen, Yiping LiAbstract:Transforming growth factor-beta (TGF-β) and bone morphogenic protein (BMP) signaling has fundamental roles in both embryonic Skeletal Development and postnatal bone homeostasis. TGF-βs and BMPs, acting on a tetrameric receptor complex, transduce signals to both the canonical Smad-dependent signaling pathway (that is, TGF-β/BMP ligands, receptors, and Smads) and the non-canonical-Smad-independent signaling pathway (that is, p38 mitogen-activated protein kinase/p38 MAPK) to regulate mesenchymal stem cell differentiation during Skeletal Development, bone formation and bone homeostasis. Both the Smad and p38 MAPK signaling pathways converge at transcription factors, for example, Runx2 to promote osteoblast differentiation and chondrocyte differentiation from mesenchymal precursor cells. TGF-β and BMP signaling is controlled by multiple factors, including the ubiquitin–proteasome system, epigenetic factors, and microRNA. Dysregulated TGF-β and BMP signaling result in a number of bone disorders in humans. Knockout or mutation of TGF-β and BMP signaling-related genes in mice leads to bone abnormalities of varying severity, which enable a better understanding of TGF-β/BMP signaling in bone and the signaling networks underlying osteoblast differentiation and bone formation. There is also crosstalk between TGF-β/BMP signaling and several critical cytokines’ signaling pathways (for example, Wnt, Hedgehog, Notch, PTHrP, and FGF) to coordinate osteogenesis, Skeletal Development, and bone homeostasis. This review summarizes the recent advances in our understanding of TGF-β/BMP signaling in osteoblast differentiation, chondrocyte differentiation, Skeletal Development, cartilage formation, bone formation, bone homeostasis, and related human bone diseases caused by the disruption of TGF-β/BMP signaling. Two families of signaling proteins represent valuable targets for human diseases associated with defects in bone and cartilage Development. Yi-Ping Li and colleagues at the University of Alabama at Birmingham have reviewed how pathways activated by transforming growth factor-β (TGF-β) and bone morphogenetic protein (BMP) help coordinate the Development and maintenance of the Skeletal system. TGF-β and BMP can promote both the construction and disassembly of bone and cartilage, and modulate the behavior of cells that form these tissues. The outcomes resulting from pathway activation are shaped by interactions between further signaling proteins and other cellular pathways, and diverse other regulatory mechanisms. Treatments targeting these activated pathways have already shown promise for repairing fractures and other bone damage, and evidence suggests that patients with osteoarthritis and other Skeletal disorders may benefit from similar approaches.
