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Natalina Quarto - One of the best experts on this subject based on the ideXlab platform.

  • Absence of Endochondral Ossification and Craniosynostosis in Posterior Frontal Cranial Sutures of Axin2-/- Mice
    PLOS ONE, 2013
    Co-Authors: Bjorn Behr, Michael T. Longaker, Natalina Quarto
    Abstract:

    During the first month of life, the murine posterior-frontal suture (PF) of the cranial vault closes through Endochondral Ossification, while other sutures remain patent. These processes are tightly regulated by canonical Wnt signaling. Low levels of active canonical Wnt signaling enable Endochondral Ossification and therefore PF-suture closure, whereas constitutive activation of canonical Wnt causes PF-suture patency. We therefore sought to test this concept with a knockout mouse model. PF-sutures of Axin2−/− mice, which resemble a state of constantly activated canonical Wnt signaling, were investigated during the physiological time course of PF-suture closure and compared in detail with wild type littermates. Histological analysis revealed that the architecture in Axin2−/− PF-sutures was significantly altered in comparison to wild type. The distance between the endocranial layers was dramatically increased and suture closure was significantly delayed. Moreover, physiological Endochondral Ossification did not occur, rather an ectopic cartilage appeared between the endocranial and ectocranial bone layers at P7 which eventually involutes at P13. Quantitative PCR analysis showed the lack of Col10α1 upregulation in Axin2−/− PF-suture. Immunohistochemistry and gene expression analysis also revealed high levels of type II collagen as compared to type I collagen and absence of Mmp-9 in the cartilage of Axin2−/− PF-suture. Moreover, TUNEL staining showed a high percentage of apoptotic chondrocytes in Axin2−/− PF-sutures at P9 and P11 as compared to wild type. These data indicated that Axin2−/− PF-sutures lack physiological Endochondral Ossification, contain ectopic cartilage and display delayed suture closure.

  • absence of Endochondral Ossification and craniosynostosis in posterior frontal cranial sutures of axin2 mice
    PLOS ONE, 2013
    Co-Authors: Michael T. Longaker, Bjorn Behr, Natalina Quarto
    Abstract:

    During the first month of life, the murine posterior-frontal suture (PF) of the cranial vault closes through Endochondral Ossification, while other sutures remain patent. These processes are tightly regulated by canonical Wnt signaling. Low levels of active canonical Wnt signaling enable Endochondral Ossification and therefore PF-suture closure, whereas constitutive activation of canonical Wnt causes PF-suture patency. We therefore sought to test this concept with a knockout mouse model. PF-sutures of Axin2−/− mice, which resemble a state of constantly activated canonical Wnt signaling, were investigated during the physiological time course of PF-suture closure and compared in detail with wild type littermates. Histological analysis revealed that the architecture in Axin2−/− PF-sutures was significantly altered in comparison to wild type. The distance between the endocranial layers was dramatically increased and suture closure was significantly delayed. Moreover, physiological Endochondral Ossification did not occur, rather an ectopic cartilage appeared between the endocranial and ectocranial bone layers at P7 which eventually involutes at P13. Quantitative PCR analysis showed the lack of Col10α1 upregulation in Axin2−/− PF-suture. Immunohistochemistry and gene expression analysis also revealed high levels of type II collagen as compared to type I collagen and absence of Mmp-9 in the cartilage of Axin2−/− PF-suture. Moreover, TUNEL staining showed a high percentage of apoptotic chondrocytes in Axin2−/− PF-sutures at P9 and P11 as compared to wild type. These data indicated that Axin2−/− PF-sutures lack physiological Endochondral Ossification, contain ectopic cartilage and display delayed suture closure.

  • craniosynostosis of coronal suture in twist1 mice occurs through Endochondral Ossification recapitulating the physiological closure of posterior frontal suture
    Frontiers in Physiology, 2011
    Co-Authors: Bjorn Behr, Michael T. Longaker, Natalina Quarto
    Abstract:

    Craniosynostosis, the premature closure of cranial suture, is a pathologic condition that affects 1/2000 live births. Saethre-Chotzen syndrome is a genetic condition characterized by craniosynostosis. The Saethre-Chotzen syndrome, which is defined by loss-of-function mutations in the TWIST gene, is the second most prevalent craniosynostosis. Although much of the genetics and phenotypes in craniosynostosis syndromes is understood, less is known about the underlying Ossification mechanism during suture closure. We have previously demonstrated that physiological closure of the posterior frontal (PF) suture occurs through Endochondral Ossification. Moreover, we revealed that antagonizing canonical Wnt signaling in the sagittal suture leads to Endochondral Ossification of the suture mesenchyme and sagittal synostosis, presumably by inhibiting Twist1. Classic Saethre-Chotzen syndrome is characterized by coronal synostosis, and the haploinsufficient Twist1+/- mice represents a suitable model for studying this syndrome. Thus, we seeked to understand the underlying Ossification process in coronal craniosynostosis in Twist1+/- mice. Our data indicate that coronal suture closure in Twist1+/- mice occurs between postnatal day 9 to 13 by Endochondral Ossification, as shown by histology, gene expression analysis and immunohistochemistry. In conclusion, this study reveals that coronal craniosynostosis in Twist1+/- mice occurs through Endochondral Ossification. Moreover, it suggests that haploinsufficency of Twist1 gene, a target of canonical Wnt-signaling, and inhibitor of chondrogenesis, mimics conditions of inactive canonical Wnt-signaling leading to craniosynostosis.

Bjorn Behr - One of the best experts on this subject based on the ideXlab platform.

  • Absence of Endochondral Ossification and Craniosynostosis in Posterior Frontal Cranial Sutures of Axin2-/- Mice
    PLOS ONE, 2013
    Co-Authors: Bjorn Behr, Michael T. Longaker, Natalina Quarto
    Abstract:

    During the first month of life, the murine posterior-frontal suture (PF) of the cranial vault closes through Endochondral Ossification, while other sutures remain patent. These processes are tightly regulated by canonical Wnt signaling. Low levels of active canonical Wnt signaling enable Endochondral Ossification and therefore PF-suture closure, whereas constitutive activation of canonical Wnt causes PF-suture patency. We therefore sought to test this concept with a knockout mouse model. PF-sutures of Axin2−/− mice, which resemble a state of constantly activated canonical Wnt signaling, were investigated during the physiological time course of PF-suture closure and compared in detail with wild type littermates. Histological analysis revealed that the architecture in Axin2−/− PF-sutures was significantly altered in comparison to wild type. The distance between the endocranial layers was dramatically increased and suture closure was significantly delayed. Moreover, physiological Endochondral Ossification did not occur, rather an ectopic cartilage appeared between the endocranial and ectocranial bone layers at P7 which eventually involutes at P13. Quantitative PCR analysis showed the lack of Col10α1 upregulation in Axin2−/− PF-suture. Immunohistochemistry and gene expression analysis also revealed high levels of type II collagen as compared to type I collagen and absence of Mmp-9 in the cartilage of Axin2−/− PF-suture. Moreover, TUNEL staining showed a high percentage of apoptotic chondrocytes in Axin2−/− PF-sutures at P9 and P11 as compared to wild type. These data indicated that Axin2−/− PF-sutures lack physiological Endochondral Ossification, contain ectopic cartilage and display delayed suture closure.

  • absence of Endochondral Ossification and craniosynostosis in posterior frontal cranial sutures of axin2 mice
    PLOS ONE, 2013
    Co-Authors: Michael T. Longaker, Bjorn Behr, Natalina Quarto
    Abstract:

    During the first month of life, the murine posterior-frontal suture (PF) of the cranial vault closes through Endochondral Ossification, while other sutures remain patent. These processes are tightly regulated by canonical Wnt signaling. Low levels of active canonical Wnt signaling enable Endochondral Ossification and therefore PF-suture closure, whereas constitutive activation of canonical Wnt causes PF-suture patency. We therefore sought to test this concept with a knockout mouse model. PF-sutures of Axin2−/− mice, which resemble a state of constantly activated canonical Wnt signaling, were investigated during the physiological time course of PF-suture closure and compared in detail with wild type littermates. Histological analysis revealed that the architecture in Axin2−/− PF-sutures was significantly altered in comparison to wild type. The distance between the endocranial layers was dramatically increased and suture closure was significantly delayed. Moreover, physiological Endochondral Ossification did not occur, rather an ectopic cartilage appeared between the endocranial and ectocranial bone layers at P7 which eventually involutes at P13. Quantitative PCR analysis showed the lack of Col10α1 upregulation in Axin2−/− PF-suture. Immunohistochemistry and gene expression analysis also revealed high levels of type II collagen as compared to type I collagen and absence of Mmp-9 in the cartilage of Axin2−/− PF-suture. Moreover, TUNEL staining showed a high percentage of apoptotic chondrocytes in Axin2−/− PF-sutures at P9 and P11 as compared to wild type. These data indicated that Axin2−/− PF-sutures lack physiological Endochondral Ossification, contain ectopic cartilage and display delayed suture closure.

  • craniosynostosis of coronal suture in twist1 mice occurs through Endochondral Ossification recapitulating the physiological closure of posterior frontal suture
    Frontiers in Physiology, 2011
    Co-Authors: Bjorn Behr, Michael T. Longaker, Natalina Quarto
    Abstract:

    Craniosynostosis, the premature closure of cranial suture, is a pathologic condition that affects 1/2000 live births. Saethre-Chotzen syndrome is a genetic condition characterized by craniosynostosis. The Saethre-Chotzen syndrome, which is defined by loss-of-function mutations in the TWIST gene, is the second most prevalent craniosynostosis. Although much of the genetics and phenotypes in craniosynostosis syndromes is understood, less is known about the underlying Ossification mechanism during suture closure. We have previously demonstrated that physiological closure of the posterior frontal (PF) suture occurs through Endochondral Ossification. Moreover, we revealed that antagonizing canonical Wnt signaling in the sagittal suture leads to Endochondral Ossification of the suture mesenchyme and sagittal synostosis, presumably by inhibiting Twist1. Classic Saethre-Chotzen syndrome is characterized by coronal synostosis, and the haploinsufficient Twist1+/- mice represents a suitable model for studying this syndrome. Thus, we seeked to understand the underlying Ossification process in coronal craniosynostosis in Twist1+/- mice. Our data indicate that coronal suture closure in Twist1+/- mice occurs between postnatal day 9 to 13 by Endochondral Ossification, as shown by histology, gene expression analysis and immunohistochemistry. In conclusion, this study reveals that coronal craniosynostosis in Twist1+/- mice occurs through Endochondral Ossification. Moreover, it suggests that haploinsufficency of Twist1 gene, a target of canonical Wnt-signaling, and inhibitor of chondrogenesis, mimics conditions of inactive canonical Wnt-signaling leading to craniosynostosis.

Michael T. Longaker - One of the best experts on this subject based on the ideXlab platform.

  • Absence of Endochondral Ossification and Craniosynostosis in Posterior Frontal Cranial Sutures of Axin2-/- Mice
    PLOS ONE, 2013
    Co-Authors: Bjorn Behr, Michael T. Longaker, Natalina Quarto
    Abstract:

    During the first month of life, the murine posterior-frontal suture (PF) of the cranial vault closes through Endochondral Ossification, while other sutures remain patent. These processes are tightly regulated by canonical Wnt signaling. Low levels of active canonical Wnt signaling enable Endochondral Ossification and therefore PF-suture closure, whereas constitutive activation of canonical Wnt causes PF-suture patency. We therefore sought to test this concept with a knockout mouse model. PF-sutures of Axin2−/− mice, which resemble a state of constantly activated canonical Wnt signaling, were investigated during the physiological time course of PF-suture closure and compared in detail with wild type littermates. Histological analysis revealed that the architecture in Axin2−/− PF-sutures was significantly altered in comparison to wild type. The distance between the endocranial layers was dramatically increased and suture closure was significantly delayed. Moreover, physiological Endochondral Ossification did not occur, rather an ectopic cartilage appeared between the endocranial and ectocranial bone layers at P7 which eventually involutes at P13. Quantitative PCR analysis showed the lack of Col10α1 upregulation in Axin2−/− PF-suture. Immunohistochemistry and gene expression analysis also revealed high levels of type II collagen as compared to type I collagen and absence of Mmp-9 in the cartilage of Axin2−/− PF-suture. Moreover, TUNEL staining showed a high percentage of apoptotic chondrocytes in Axin2−/− PF-sutures at P9 and P11 as compared to wild type. These data indicated that Axin2−/− PF-sutures lack physiological Endochondral Ossification, contain ectopic cartilage and display delayed suture closure.

  • absence of Endochondral Ossification and craniosynostosis in posterior frontal cranial sutures of axin2 mice
    PLOS ONE, 2013
    Co-Authors: Michael T. Longaker, Bjorn Behr, Natalina Quarto
    Abstract:

    During the first month of life, the murine posterior-frontal suture (PF) of the cranial vault closes through Endochondral Ossification, while other sutures remain patent. These processes are tightly regulated by canonical Wnt signaling. Low levels of active canonical Wnt signaling enable Endochondral Ossification and therefore PF-suture closure, whereas constitutive activation of canonical Wnt causes PF-suture patency. We therefore sought to test this concept with a knockout mouse model. PF-sutures of Axin2−/− mice, which resemble a state of constantly activated canonical Wnt signaling, were investigated during the physiological time course of PF-suture closure and compared in detail with wild type littermates. Histological analysis revealed that the architecture in Axin2−/− PF-sutures was significantly altered in comparison to wild type. The distance between the endocranial layers was dramatically increased and suture closure was significantly delayed. Moreover, physiological Endochondral Ossification did not occur, rather an ectopic cartilage appeared between the endocranial and ectocranial bone layers at P7 which eventually involutes at P13. Quantitative PCR analysis showed the lack of Col10α1 upregulation in Axin2−/− PF-suture. Immunohistochemistry and gene expression analysis also revealed high levels of type II collagen as compared to type I collagen and absence of Mmp-9 in the cartilage of Axin2−/− PF-suture. Moreover, TUNEL staining showed a high percentage of apoptotic chondrocytes in Axin2−/− PF-sutures at P9 and P11 as compared to wild type. These data indicated that Axin2−/− PF-sutures lack physiological Endochondral Ossification, contain ectopic cartilage and display delayed suture closure.

  • craniosynostosis of coronal suture in twist1 mice occurs through Endochondral Ossification recapitulating the physiological closure of posterior frontal suture
    Frontiers in Physiology, 2011
    Co-Authors: Bjorn Behr, Michael T. Longaker, Natalina Quarto
    Abstract:

    Craniosynostosis, the premature closure of cranial suture, is a pathologic condition that affects 1/2000 live births. Saethre-Chotzen syndrome is a genetic condition characterized by craniosynostosis. The Saethre-Chotzen syndrome, which is defined by loss-of-function mutations in the TWIST gene, is the second most prevalent craniosynostosis. Although much of the genetics and phenotypes in craniosynostosis syndromes is understood, less is known about the underlying Ossification mechanism during suture closure. We have previously demonstrated that physiological closure of the posterior frontal (PF) suture occurs through Endochondral Ossification. Moreover, we revealed that antagonizing canonical Wnt signaling in the sagittal suture leads to Endochondral Ossification of the suture mesenchyme and sagittal synostosis, presumably by inhibiting Twist1. Classic Saethre-Chotzen syndrome is characterized by coronal synostosis, and the haploinsufficient Twist1+/- mice represents a suitable model for studying this syndrome. Thus, we seeked to understand the underlying Ossification process in coronal craniosynostosis in Twist1+/- mice. Our data indicate that coronal suture closure in Twist1+/- mice occurs between postnatal day 9 to 13 by Endochondral Ossification, as shown by histology, gene expression analysis and immunohistochemistry. In conclusion, this study reveals that coronal craniosynostosis in Twist1+/- mice occurs through Endochondral Ossification. Moreover, it suggests that haploinsufficency of Twist1 gene, a target of canonical Wnt-signaling, and inhibitor of chondrogenesis, mimics conditions of inactive canonical Wnt-signaling leading to craniosynostosis.

Adele L Boskey - One of the best experts on this subject based on the ideXlab platform.

  • adam17 controls Endochondral Ossification by regulating terminal differentiation of chondrocytes
    Molecular and Cellular Biology, 2013
    Co-Authors: Katherine Hall, Daniel Hill, Miguel Otero, Darren A Plumb, Dara Froemel, Cecilia L Dragomir, Thorsten Maretzky, Adele L Boskey
    Abstract:

    Endochondral Ossification is a highly regulated process that relies on properly orchestrated cell-cell interactions in the developing growth plate. This study is focused on understanding the role of a crucial regulator of cell-cell interactions, the membrane-anchored metalloproteinase ADAM17, in Endochondral Ossification. ADAM17 releases growth factors, cytokines, and other membrane proteins from cells and is essential for epidermal growth factor receptor (EGFR) signaling and for processing tumor necrosis factor alpha. Here, we report that mice lacking ADAM17 in chondrocytes (A17ΔCh) have a significantly expanded zone of hypertrophic chondrocytes in the growth plate and retarded growth of long bones. This abnormality is caused by an accumulation of the most terminally differentiated type of chondrocytes that produces a calcified matrix. Inactivation of ADAM17 in osteoclasts or endothelial cells does not affect the zone of hypertrophic chondrocytes, suggesting that the main role of ADAM17 in the growth plate is in chondrocytes. This notion is further supported by in vitro experiments showing enhanced hypertrophic differentiation of primary chondrocytes lacking Adam17. The enlarged zone of hypertrophic chondrocytes in A17ΔCh mice resembles that described in mice with mutant EGFR signaling or lack of its ligand transforming growth factor α (TGFα), suggesting that ADAM17 regulates terminal differentiation of chondrocytes during Endochondral Ossification by activating the TGFα/EGFR signaling axis.

Riko Nishimura - One of the best experts on this subject based on the ideXlab platform.

  • transcriptional network controlling Endochondral Ossification
    Journal of Bone Metabolism, 2017
    Co-Authors: Kenji Hata, Yoshifumi Takahata, Tomohiko Murakami, Riko Nishimura
    Abstract:

    : Endochondral Ossification is the fundamental process of skeletal development in vertebrates. Chondrocytes undergo sequential steps of differentiation, including mesenchymal condensation, proliferation, hypertrophy, and mineralization. These steps, which are required for the morphological and functional changes in differentiating chondrocytes, are strictly regulated by a complex transcriptional network. Biochemical and mice genetic studies identified chondrogenic transcription factors critical for Endochondral Ossification. The transcription factor sex-determining region Y (SRY)-box 9 (Sox9) is essential for early chondrogenesis, and impaired Sox9 function causes severe chondrodysplasia in humans and mice. In addition, recent genome-wide chromatin immunoprecipitation-sequencing studies revealed the precise regulatory mechanism of Sox9 during early chondrogenesis. Runt-related transcription factor 2 promotes chondrocyte hypertrophy and terminal differentiation. Interestingly, endoplasmic reticulum (ER) stress-related transcription factors have recently emerged as novel regulators of chondrocyte differentiation. Here we review the transcriptional mechanisms that regulate Endochondral Ossification, with a focus on Sox9.

  • the transcription factor foxc1 is necessary for ihh gli2 regulated Endochondral Ossification
    Nature Communications, 2015
    Co-Authors: Kenji Hata, Rikako Takashima, Michiko Yoshida, Yoshifumi Takahata, Tomohiko Murakami, Eriko Nakamura, Sachiko Iseki, Teruko Takanoyamamoto, Riko Nishimura
    Abstract:

    Skeletal development relies on Endochondral Ossification. Here the authors show that transcription factors Foxc1 and Gli2 interact to modulate expression of Ihh target genes that control Endochondral Ossification, and that disruption of this interaction partly underlies skeletal disorders in the Axenfeld–Rieger syndrome.

  • Regulation of Endochondral Ossification by transcription factors
    Journal of Oral Biosciences, 2012
    Co-Authors: Riko Nishimura, Kenji Hata, Rikako Takashima, Michiko Yoshida, Toshiyuki Yoneda
    Abstract:

    Abstract Endochondral Ossification is temporospatially regulated by several growth factors, cytokines, and hormones that control their downstream signaling pathways and specific transcription factors. Genetic studies have identified several transcription factors necessary for Endochondral Ossification, including Sox9 family members, Runx2 family members, and Osterix. In addition, biochemical investigation has demonstrated how these transcription factors regulate Endochondral Ossification. Importantly, these transcription factors form a complex but harmonized network system during Endochondral Ossification. We recently demonstrated the multi-functional role of Sox9 in Endochondral Ossification. Moreover, we found that the Runx2-Osterix linkage was critical for Endochondral Ossification.

  • osterix regulates calcification and degradation of chondrogenic matrices through matrix metalloproteinase 13 mmp13 expression in association with transcription factor runx2 during Endochondral Ossification
    Journal of Biological Chemistry, 2012
    Co-Authors: Riko Nishimura, Makoto Wakabayashi, Takuma Matsubara, Shiho Honma, Go Shioi, Satoshi Wakisaka, Akira Yamaguchi, Hiroshi Kiyonari, Kenji Hata, Noriyuki Tsumaki
    Abstract:

    Endochondral Ossification is temporally and spatially regulated by several critical transcription factors, including Sox9, Runx2, and Runx3. Although the molecular mechanisms that control the late stages of Endochondral Ossification (e.g. calcification) are physiologically and pathologically important, these precise regulatory mechanisms remain unclear. Here, we demonstrate that Osterix is an essential transcription factor for Endochondral Ossification that functions downstream of Runx2. The global and conditional Osterix-deficient mice studied here exhibited a defect of cartilage-matrix Ossification and matrix vesicle formation. Importantly, Osterix deficiencies caused the arrest of Endochondral Ossification at the hypertrophic stage. Microarray analysis revealed that matrix metallopeptidase 13 (MMP13) is an important target of Osterix. We also showed that there exists a physical interaction between Osterix and Runx2 and that these proteins function cooperatively to induce MMP13 during chondrocyte differentiation. Most interestingly, the introduction of MMP13 stimulated the calcification of matrices in Osterix-deficient mouse limb bud cells. Our results demonstrated that Osterix was essential to Endochondral Ossification and revealed that the physical and functional interaction between Osterix and Runx2 were necessary for the induction of MMP13 during Endochondral Ossification.

  • Regulation of Endochondral Ossification by transcription factors
    Frontiers in Bioscience, 2012
    Co-Authors: Riko Nishimura, Makoto Wakabayashi, Kenji Hata, Rikako Takashima, Katsuhiko Amano, Yoko Takigawa, Toshiyuki Yoneda
    Abstract:

    Abstract Endochondral Ossification is very unique and complex biological event which is associated with skeletal development and tissue partnering. Genetic studies and gene-targeting approaches identified several transcription factors that play important roles in Endochondral Ossification. These transcription factors sequentially and harmoniously regulate each step of Endochondral Ossification, and consequently maintain the spatio-temporal control of the program. Importantly, these transcription factors form large protein complex to control chromatin remodeling, histone modification, transcription and splicing steps during Endochondral Ossification. It is also important to understand how these transcription factors regulate expression of their target genes. Biochemical and molecular cloning techniques largely contributed to identification of the components of the transcriptional complex and the target genes. Most recently, importance of endoplasmic reticulum (ER) stress in Endochondral Ossification has been reported. A transcription factor, BBF2H7, functions as an ER stress sensor in chondrocytes through regulation of appropriate secretion of chondrogenic matrices. We would like to discuss how the transcription factors regulate Endochondral Ossification.