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Tim Jm Welting - One of the best experts on this subject based on the ideXlab platform.

  • The antiviral protein viperin regulates Chondrogenic Differentiation via CXCL10 protein secretion.
    The Journal of biological chemistry, 2019
    Co-Authors: Mandy M. F. Steinbusch, Marjolein M. J. Caron, D.a. Surtel, Franziska Friedrich, Lodewijk W. Van Rhijn, Bernhard Zabel, Guus G. H. Van Den Akker, Paul Van Dijk, Mandy J. Peffers, Tim Jm Welting
    Abstract:

    Viperin (also known as radical SAM domain-containing 2 (RSAD2)) is an interferon-inducible and evolutionary conserved protein that participates in the cell's innate immune response against a number of viruses. Viperin mRNA is a substrate for endoribonucleolytic cleavage by RNase mitochondrial RNA processing (MRP) and mutations in the RNase MRP small nucleolar RNA (snoRNA) subunit of the RNase MRP complex cause cartilage-hair hypoplasia (CHH), a human developmental condition characterized by metaphyseal chondrodysplasia and severe dwarfism. It is unknown how CHH-pathogenic mutations in RNase MRP snoRNA interfere with skeletal development, and aberrant processing of RNase MRP substrate RNAs is thought to be involved. We hypothesized that viperin plays a role in Chondrogenic Differentiation. Using immunohistochemistry, real-time quantitative PCR, immunoblotting, ELISA, siRNA-mediated gene silencing, plasmid-mediated gene overexpression, label-free MS proteomics, and promoter reporter bioluminescence assays, we discovered here that viperin is expressed in differentiating chondrocytic cells and regulates their protein secretion and the outcome of Chondrogenic Differentiation by influencing transforming growth factor β (TGF-β)/SMAD family 2/3 (SMAD2/3) activity via C-X-C motif chemokine ligand 10 (CXCL10). Of note, we observed disturbances in this viperin-CXCL10-TGF-β/SMAD2/3 axis in CHH chondrocytic cells. Our results indicate that the antiviral protein viperin controls Chondrogenic Differentiation by influencing secretion of soluble proteins and identify a molecular route that may explain impaired Chondrogenic Differentiation of cells from individuals with CHH.

  • The antiviral protein viperin regulates Chondrogenic Differentiation via CXCL10 protein secretion.
    'American Society for Biochemistry & Molecular Biology (ASBMB)', 2019
    Co-Authors: Mandy M. F. Steinbusch, Marjolein M. J. Caron, Don Am Surtel, Guus Gh ,van Den Akker, Van Dijk, Paul J, Friedrich Franziska, Zabel Bernhard, Van Rhijn, Lodewijk W, Peffers, Mandy J, Tim Jm Welting
    Abstract:

    Viperin (also known as radical SAM domain-containing 2, RSAD2) is an interferon-inducible and evolutionary conserved protein that participates in the cell's innate immune response against a number of viruses. Viperin mRNA is a substrate for endoribonucleolytic cleavage by RNase mitochondrial RNA processing (MRP) and mutations in the RMRP small nucleolar RNA (snoRNA) subunit of the RNase MRP complex cause cartilage-hair hypoplasia (CHH), a human developmental condition characterized by metaphyseal chondrodysplasia and severe dwarfism. It is unknown how CHH-pathogenic mutations in RMRP snoRNA interfere with skeletal development and aberrant processing of RNase MRP substrate RNAs is thought to be involved. We hypothesized that viperin plays a role in Chondrogenic Differentiation. Using immunohistochemistry, RT-qPCR, immunoblotting, ELISA, siRNA-mediated gene silencing, plasmid-mediated gene overexpression, label-free mass-spectrometry proteomics and promoter reporter bioluminescence assays, we discovered here that viperin is expressed in differentiating chondrocytic cells and regulates their protein secretion and the outcome of Chondrogenic Differentiation by influencing transforming growth factor β (TGF-β)/SMAD family 2/3 (SMAD2/3) activity via C-X-C motif chemokine ligand 10 (CXCL10). Of note, we observed disturbances in this viperin-CXCL10-TGF-β/SMAD2/3 axis in CHH chondrocytic cells. Our results indicate that the anti-viral protein viperin controls Chondrogenic Differentiation by influencing secretion of soluble proteins and identify a molecular route that may explain impaired Chondrogenic Differentiation of cells from individuals with CHH

  • Osmolarity determines the in vitro Chondrogenic Differentiation capacity of progenitor cells via nuclear factor of activated T-cells 5
    Bone, 2012
    Co-Authors: Marjolein M. J. Caron, Holger Jahr, Lodewijk W. Van Rhijn, Pieter J Emans, Anna E. Van Der Windt, Tim Jm Welting
    Abstract:

    Abstract Introduction Previous studies have shown that human articular chondrocytes in vitro are osmolarity-responsive and increase matrix synthesis under cartilage-specific physiological osmolarity. The effects of increased osmolarity on chondrogenesis of progenitor cells in vitro are largely unknown. We therefore aimed to elucidate whether hyperosmolarity facilitates their Chondrogenic Differentiation and whether Nfat5 is involved. Materials and methods ATDC5 cells and human bone marrow stem cells (hBMSCs) were differentiated in the Chondrogenic lineage in control and increased osmolarity conditions. Chondrogenic outcome was measured by gene- and protein expression analysis. RNAi was used to determine the role of Nfat5 in Chondrogenic Differentiation under normal and increased osmolarity. Results Increasing the osmolarity of Differentiation medium with 100 mOsm resulted in significantly increased Chondrogenic marker expression (Col2a1, Col10a1, Acan, Sox9, Runx2 and GAGs) during Chondrogenic Differentiation of the two chondroprogenitors, ATDC5 and hBMSCs. Nfat5 knockdown under both control and increased osmolarity affected Chondrogenic Differentiation and suppressed the osmolarity-induced Chondrogenic induction. Knockdown of Nfat5 in early Differentiation significantly decreased early Sox9 expression, whereas knockdown of Sox9 in early Differentiation did not affect early Nfat5 expression. Conclusions Increasing the osmolarity of Chondrogenic culture media by 100 mOsm significantly increased Chondrogenic gene expression during the course of Chondrogenic Differentiation of progenitor cells. Nfat5 may be involved in regulating Chondrogenic Differentiation of these cells under both normal and increased osmolarities and might regulate Chondrogenic Differentiation through influencing early Sox9 expression.

  • activation of nf κb p65 facilitates early Chondrogenic Differentiation during endochondral ossification
    PLOS ONE, 2012
    Co-Authors: M Caron, D.a. Surtel, Tim Jm Welting, Pieter J Emans, A Cremers, Jan Willem Voncken, Lodewijk W Van Rhijn
    Abstract:

    Background NF-κB/p65 has been reported to be involved in regulation of Chondrogenic Differentiation. However, its function in relation to key Chondrogenic factor Sox9 and onset of chondrogenesis during endochondral ossification is poorly understood. We hypothesized that the early onset of Chondrogenic Differentiation is initiated by transient NF-κB/p65 signaling. Methodology/Principal Findings The role of NF-κB/p65 in early chondrogenesis was investigated in different in vitro, ex vivo and in vivo endochondral models: ATDC5 cells, hBMSCs, chicken periosteal explants and growth plates of 6 weeks old mice. NF-κB/p65 activation was manipulated using pharmacological inhibitors, RNAi and activating agents. Gene expression and protein expression analysis, and (immuno)histochemical stainings were employed to determine the role of NF-κB/p65 in the Chondrogenic phase of endochondral development. Our data show that Chondrogenic Differentiation is facilitated by early transient activation of NF-κB/p65. NF-κB/p65-mediated signaling determines early expression of Sox9 and facilitates the subsequent Chondrogenic Differentiation programming by signaling through key Chondrogenic pathways. Conclusions/Significance The presented data demonstrate that NF-κB/p65 signaling, as well as its intensity and timing, represents one of the transcriptional regulatory mechanisms of the Chondrogenic developmental program of chondroprogenitor cells during endochondral ossification. Importantly, these results provide novel possibilities to improve the success of cartilage and bone regenerative techniques.

Mandy M. F. Steinbusch - One of the best experts on this subject based on the ideXlab platform.

  • The antiviral protein viperin regulates Chondrogenic Differentiation via CXCL10 protein secretion.
    The Journal of biological chemistry, 2019
    Co-Authors: Mandy M. F. Steinbusch, Marjolein M. J. Caron, D.a. Surtel, Franziska Friedrich, Lodewijk W. Van Rhijn, Bernhard Zabel, Guus G. H. Van Den Akker, Paul Van Dijk, Mandy J. Peffers, Tim Jm Welting
    Abstract:

    Viperin (also known as radical SAM domain-containing 2 (RSAD2)) is an interferon-inducible and evolutionary conserved protein that participates in the cell's innate immune response against a number of viruses. Viperin mRNA is a substrate for endoribonucleolytic cleavage by RNase mitochondrial RNA processing (MRP) and mutations in the RNase MRP small nucleolar RNA (snoRNA) subunit of the RNase MRP complex cause cartilage-hair hypoplasia (CHH), a human developmental condition characterized by metaphyseal chondrodysplasia and severe dwarfism. It is unknown how CHH-pathogenic mutations in RNase MRP snoRNA interfere with skeletal development, and aberrant processing of RNase MRP substrate RNAs is thought to be involved. We hypothesized that viperin plays a role in Chondrogenic Differentiation. Using immunohistochemistry, real-time quantitative PCR, immunoblotting, ELISA, siRNA-mediated gene silencing, plasmid-mediated gene overexpression, label-free MS proteomics, and promoter reporter bioluminescence assays, we discovered here that viperin is expressed in differentiating chondrocytic cells and regulates their protein secretion and the outcome of Chondrogenic Differentiation by influencing transforming growth factor β (TGF-β)/SMAD family 2/3 (SMAD2/3) activity via C-X-C motif chemokine ligand 10 (CXCL10). Of note, we observed disturbances in this viperin-CXCL10-TGF-β/SMAD2/3 axis in CHH chondrocytic cells. Our results indicate that the antiviral protein viperin controls Chondrogenic Differentiation by influencing secretion of soluble proteins and identify a molecular route that may explain impaired Chondrogenic Differentiation of cells from individuals with CHH.

  • The antiviral protein viperin regulates Chondrogenic Differentiation via CXCL10 protein secretion.
    'American Society for Biochemistry & Molecular Biology (ASBMB)', 2019
    Co-Authors: Mandy M. F. Steinbusch, Marjolein M. J. Caron, Don Am Surtel, Guus Gh ,van Den Akker, Van Dijk, Paul J, Friedrich Franziska, Zabel Bernhard, Van Rhijn, Lodewijk W, Peffers, Mandy J, Tim Jm Welting
    Abstract:

    Viperin (also known as radical SAM domain-containing 2, RSAD2) is an interferon-inducible and evolutionary conserved protein that participates in the cell's innate immune response against a number of viruses. Viperin mRNA is a substrate for endoribonucleolytic cleavage by RNase mitochondrial RNA processing (MRP) and mutations in the RMRP small nucleolar RNA (snoRNA) subunit of the RNase MRP complex cause cartilage-hair hypoplasia (CHH), a human developmental condition characterized by metaphyseal chondrodysplasia and severe dwarfism. It is unknown how CHH-pathogenic mutations in RMRP snoRNA interfere with skeletal development and aberrant processing of RNase MRP substrate RNAs is thought to be involved. We hypothesized that viperin plays a role in Chondrogenic Differentiation. Using immunohistochemistry, RT-qPCR, immunoblotting, ELISA, siRNA-mediated gene silencing, plasmid-mediated gene overexpression, label-free mass-spectrometry proteomics and promoter reporter bioluminescence assays, we discovered here that viperin is expressed in differentiating chondrocytic cells and regulates their protein secretion and the outcome of Chondrogenic Differentiation by influencing transforming growth factor β (TGF-β)/SMAD family 2/3 (SMAD2/3) activity via C-X-C motif chemokine ligand 10 (CXCL10). Of note, we observed disturbances in this viperin-CXCL10-TGF-β/SMAD2/3 axis in CHH chondrocytic cells. Our results indicate that the anti-viral protein viperin controls Chondrogenic Differentiation by influencing secretion of soluble proteins and identify a molecular route that may explain impaired Chondrogenic Differentiation of cells from individuals with CHH

  • Expression of RMRP RNA is regulated in chondrocyte hypertrophy and determines Chondrogenic Differentiation.
    Scientific reports, 2017
    Co-Authors: Mandy M. F. Steinbusch, Marjolein M. J. Caron, D.a. Surtel, Franziska Friedrich, Ekkehart Lausch, Ger J. M. Pruijn, Wouter Verhesen, Blanche Schroen, Lodewijk W. Van Rhijn, Bernhard Zabel
    Abstract:

    Mutations in the RMRP-gene, encoding the lncRNA component of the RNase MRP complex, are the origin of cartilage-hair hypoplasia. Cartilage-hair hypoplasia is associated with severe dwarfism caused by impaired skeletal development. However, it is not clear why mutations in RMRP RNA lead to skeletal dysplasia. Since Chondrogenic Differentiation of the growth plate is required for development of long bones, we hypothesized that RMRP RNA plays a pivotal role in Chondrogenic Differentiation. Expression of Rmrp RNA and RNase MRP protein subunits was detected in the murine growth plate and during the course of Chondrogenic Differentiation of ATDC5 cultures, where Rmrp RNA expression was found to be correlated with chondrocyte hypertrophy. Genetic interference with Rmrp RNA expression in ATDC5 cultures caused a deregulation of Chondrogenic Differentiation, with a prominent impact on hypertrophy and changes in pre-rRNA processing and rRNA levels. Promoter reporter studies showed that Rmrp RNA expression responds to Chondrogenic morphogens. Chondrogenic trans-Differentiation of cartilage-hair hypoplasia fibroblasts was impaired with a pronounced impact on hypertrophic Differentiation. Together, our data show that RMRP RNA expression is regulated during different stages of Chondrogenic Differentiation and indicate that RMRP RNA may play a pivotal role in chondrocyte hypertrophy, with potential consequences for CHH pathobiology.

Marjolein M. J. Caron - One of the best experts on this subject based on the ideXlab platform.

  • The antiviral protein viperin regulates Chondrogenic Differentiation via CXCL10 protein secretion.
    The Journal of biological chemistry, 2019
    Co-Authors: Mandy M. F. Steinbusch, Marjolein M. J. Caron, D.a. Surtel, Franziska Friedrich, Lodewijk W. Van Rhijn, Bernhard Zabel, Guus G. H. Van Den Akker, Paul Van Dijk, Mandy J. Peffers, Tim Jm Welting
    Abstract:

    Viperin (also known as radical SAM domain-containing 2 (RSAD2)) is an interferon-inducible and evolutionary conserved protein that participates in the cell's innate immune response against a number of viruses. Viperin mRNA is a substrate for endoribonucleolytic cleavage by RNase mitochondrial RNA processing (MRP) and mutations in the RNase MRP small nucleolar RNA (snoRNA) subunit of the RNase MRP complex cause cartilage-hair hypoplasia (CHH), a human developmental condition characterized by metaphyseal chondrodysplasia and severe dwarfism. It is unknown how CHH-pathogenic mutations in RNase MRP snoRNA interfere with skeletal development, and aberrant processing of RNase MRP substrate RNAs is thought to be involved. We hypothesized that viperin plays a role in Chondrogenic Differentiation. Using immunohistochemistry, real-time quantitative PCR, immunoblotting, ELISA, siRNA-mediated gene silencing, plasmid-mediated gene overexpression, label-free MS proteomics, and promoter reporter bioluminescence assays, we discovered here that viperin is expressed in differentiating chondrocytic cells and regulates their protein secretion and the outcome of Chondrogenic Differentiation by influencing transforming growth factor β (TGF-β)/SMAD family 2/3 (SMAD2/3) activity via C-X-C motif chemokine ligand 10 (CXCL10). Of note, we observed disturbances in this viperin-CXCL10-TGF-β/SMAD2/3 axis in CHH chondrocytic cells. Our results indicate that the antiviral protein viperin controls Chondrogenic Differentiation by influencing secretion of soluble proteins and identify a molecular route that may explain impaired Chondrogenic Differentiation of cells from individuals with CHH.

  • The antiviral protein viperin regulates Chondrogenic Differentiation via CXCL10 protein secretion.
    'American Society for Biochemistry & Molecular Biology (ASBMB)', 2019
    Co-Authors: Mandy M. F. Steinbusch, Marjolein M. J. Caron, Don Am Surtel, Guus Gh ,van Den Akker, Van Dijk, Paul J, Friedrich Franziska, Zabel Bernhard, Van Rhijn, Lodewijk W, Peffers, Mandy J, Tim Jm Welting
    Abstract:

    Viperin (also known as radical SAM domain-containing 2, RSAD2) is an interferon-inducible and evolutionary conserved protein that participates in the cell's innate immune response against a number of viruses. Viperin mRNA is a substrate for endoribonucleolytic cleavage by RNase mitochondrial RNA processing (MRP) and mutations in the RMRP small nucleolar RNA (snoRNA) subunit of the RNase MRP complex cause cartilage-hair hypoplasia (CHH), a human developmental condition characterized by metaphyseal chondrodysplasia and severe dwarfism. It is unknown how CHH-pathogenic mutations in RMRP snoRNA interfere with skeletal development and aberrant processing of RNase MRP substrate RNAs is thought to be involved. We hypothesized that viperin plays a role in Chondrogenic Differentiation. Using immunohistochemistry, RT-qPCR, immunoblotting, ELISA, siRNA-mediated gene silencing, plasmid-mediated gene overexpression, label-free mass-spectrometry proteomics and promoter reporter bioluminescence assays, we discovered here that viperin is expressed in differentiating chondrocytic cells and regulates their protein secretion and the outcome of Chondrogenic Differentiation by influencing transforming growth factor β (TGF-β)/SMAD family 2/3 (SMAD2/3) activity via C-X-C motif chemokine ligand 10 (CXCL10). Of note, we observed disturbances in this viperin-CXCL10-TGF-β/SMAD2/3 axis in CHH chondrocytic cells. Our results indicate that the anti-viral protein viperin controls Chondrogenic Differentiation by influencing secretion of soluble proteins and identify a molecular route that may explain impaired Chondrogenic Differentiation of cells from individuals with CHH

  • Expression of RMRP RNA is regulated in chondrocyte hypertrophy and determines Chondrogenic Differentiation.
    Scientific reports, 2017
    Co-Authors: Mandy M. F. Steinbusch, Marjolein M. J. Caron, D.a. Surtel, Franziska Friedrich, Ekkehart Lausch, Ger J. M. Pruijn, Wouter Verhesen, Blanche Schroen, Lodewijk W. Van Rhijn, Bernhard Zabel
    Abstract:

    Mutations in the RMRP-gene, encoding the lncRNA component of the RNase MRP complex, are the origin of cartilage-hair hypoplasia. Cartilage-hair hypoplasia is associated with severe dwarfism caused by impaired skeletal development. However, it is not clear why mutations in RMRP RNA lead to skeletal dysplasia. Since Chondrogenic Differentiation of the growth plate is required for development of long bones, we hypothesized that RMRP RNA plays a pivotal role in Chondrogenic Differentiation. Expression of Rmrp RNA and RNase MRP protein subunits was detected in the murine growth plate and during the course of Chondrogenic Differentiation of ATDC5 cultures, where Rmrp RNA expression was found to be correlated with chondrocyte hypertrophy. Genetic interference with Rmrp RNA expression in ATDC5 cultures caused a deregulation of Chondrogenic Differentiation, with a prominent impact on hypertrophy and changes in pre-rRNA processing and rRNA levels. Promoter reporter studies showed that Rmrp RNA expression responds to Chondrogenic morphogens. Chondrogenic trans-Differentiation of cartilage-hair hypoplasia fibroblasts was impaired with a pronounced impact on hypertrophic Differentiation. Together, our data show that RMRP RNA expression is regulated during different stages of Chondrogenic Differentiation and indicate that RMRP RNA may play a pivotal role in chondrocyte hypertrophy, with potential consequences for CHH pathobiology.

  • Osmolarity determines the in vitro Chondrogenic Differentiation capacity of progenitor cells via nuclear factor of activated T-cells 5
    Bone, 2012
    Co-Authors: Marjolein M. J. Caron, Holger Jahr, Lodewijk W. Van Rhijn, Pieter J Emans, Anna E. Van Der Windt, Tim Jm Welting
    Abstract:

    Abstract Introduction Previous studies have shown that human articular chondrocytes in vitro are osmolarity-responsive and increase matrix synthesis under cartilage-specific physiological osmolarity. The effects of increased osmolarity on chondrogenesis of progenitor cells in vitro are largely unknown. We therefore aimed to elucidate whether hyperosmolarity facilitates their Chondrogenic Differentiation and whether Nfat5 is involved. Materials and methods ATDC5 cells and human bone marrow stem cells (hBMSCs) were differentiated in the Chondrogenic lineage in control and increased osmolarity conditions. Chondrogenic outcome was measured by gene- and protein expression analysis. RNAi was used to determine the role of Nfat5 in Chondrogenic Differentiation under normal and increased osmolarity. Results Increasing the osmolarity of Differentiation medium with 100 mOsm resulted in significantly increased Chondrogenic marker expression (Col2a1, Col10a1, Acan, Sox9, Runx2 and GAGs) during Chondrogenic Differentiation of the two chondroprogenitors, ATDC5 and hBMSCs. Nfat5 knockdown under both control and increased osmolarity affected Chondrogenic Differentiation and suppressed the osmolarity-induced Chondrogenic induction. Knockdown of Nfat5 in early Differentiation significantly decreased early Sox9 expression, whereas knockdown of Sox9 in early Differentiation did not affect early Nfat5 expression. Conclusions Increasing the osmolarity of Chondrogenic culture media by 100 mOsm significantly increased Chondrogenic gene expression during the course of Chondrogenic Differentiation of progenitor cells. Nfat5 may be involved in regulating Chondrogenic Differentiation of these cells under both normal and increased osmolarities and might regulate Chondrogenic Differentiation through influencing early Sox9 expression.

D.a. Surtel - One of the best experts on this subject based on the ideXlab platform.

  • The antiviral protein viperin regulates Chondrogenic Differentiation via CXCL10 protein secretion.
    The Journal of biological chemistry, 2019
    Co-Authors: Mandy M. F. Steinbusch, Marjolein M. J. Caron, D.a. Surtel, Franziska Friedrich, Lodewijk W. Van Rhijn, Bernhard Zabel, Guus G. H. Van Den Akker, Paul Van Dijk, Mandy J. Peffers, Tim Jm Welting
    Abstract:

    Viperin (also known as radical SAM domain-containing 2 (RSAD2)) is an interferon-inducible and evolutionary conserved protein that participates in the cell's innate immune response against a number of viruses. Viperin mRNA is a substrate for endoribonucleolytic cleavage by RNase mitochondrial RNA processing (MRP) and mutations in the RNase MRP small nucleolar RNA (snoRNA) subunit of the RNase MRP complex cause cartilage-hair hypoplasia (CHH), a human developmental condition characterized by metaphyseal chondrodysplasia and severe dwarfism. It is unknown how CHH-pathogenic mutations in RNase MRP snoRNA interfere with skeletal development, and aberrant processing of RNase MRP substrate RNAs is thought to be involved. We hypothesized that viperin plays a role in Chondrogenic Differentiation. Using immunohistochemistry, real-time quantitative PCR, immunoblotting, ELISA, siRNA-mediated gene silencing, plasmid-mediated gene overexpression, label-free MS proteomics, and promoter reporter bioluminescence assays, we discovered here that viperin is expressed in differentiating chondrocytic cells and regulates their protein secretion and the outcome of Chondrogenic Differentiation by influencing transforming growth factor β (TGF-β)/SMAD family 2/3 (SMAD2/3) activity via C-X-C motif chemokine ligand 10 (CXCL10). Of note, we observed disturbances in this viperin-CXCL10-TGF-β/SMAD2/3 axis in CHH chondrocytic cells. Our results indicate that the antiviral protein viperin controls Chondrogenic Differentiation by influencing secretion of soluble proteins and identify a molecular route that may explain impaired Chondrogenic Differentiation of cells from individuals with CHH.

  • Expression of RMRP RNA is regulated in chondrocyte hypertrophy and determines Chondrogenic Differentiation.
    Scientific reports, 2017
    Co-Authors: Mandy M. F. Steinbusch, Marjolein M. J. Caron, D.a. Surtel, Franziska Friedrich, Ekkehart Lausch, Ger J. M. Pruijn, Wouter Verhesen, Blanche Schroen, Lodewijk W. Van Rhijn, Bernhard Zabel
    Abstract:

    Mutations in the RMRP-gene, encoding the lncRNA component of the RNase MRP complex, are the origin of cartilage-hair hypoplasia. Cartilage-hair hypoplasia is associated with severe dwarfism caused by impaired skeletal development. However, it is not clear why mutations in RMRP RNA lead to skeletal dysplasia. Since Chondrogenic Differentiation of the growth plate is required for development of long bones, we hypothesized that RMRP RNA plays a pivotal role in Chondrogenic Differentiation. Expression of Rmrp RNA and RNase MRP protein subunits was detected in the murine growth plate and during the course of Chondrogenic Differentiation of ATDC5 cultures, where Rmrp RNA expression was found to be correlated with chondrocyte hypertrophy. Genetic interference with Rmrp RNA expression in ATDC5 cultures caused a deregulation of Chondrogenic Differentiation, with a prominent impact on hypertrophy and changes in pre-rRNA processing and rRNA levels. Promoter reporter studies showed that Rmrp RNA expression responds to Chondrogenic morphogens. Chondrogenic trans-Differentiation of cartilage-hair hypoplasia fibroblasts was impaired with a pronounced impact on hypertrophic Differentiation. Together, our data show that RMRP RNA expression is regulated during different stages of Chondrogenic Differentiation and indicate that RMRP RNA may play a pivotal role in chondrocyte hypertrophy, with potential consequences for CHH pathobiology.

  • activation of nf κb p65 facilitates early Chondrogenic Differentiation during endochondral ossification
    PLOS ONE, 2012
    Co-Authors: M Caron, D.a. Surtel, Tim Jm Welting, Pieter J Emans, A Cremers, Jan Willem Voncken, Lodewijk W Van Rhijn
    Abstract:

    Background NF-κB/p65 has been reported to be involved in regulation of Chondrogenic Differentiation. However, its function in relation to key Chondrogenic factor Sox9 and onset of chondrogenesis during endochondral ossification is poorly understood. We hypothesized that the early onset of Chondrogenic Differentiation is initiated by transient NF-κB/p65 signaling. Methodology/Principal Findings The role of NF-κB/p65 in early chondrogenesis was investigated in different in vitro, ex vivo and in vivo endochondral models: ATDC5 cells, hBMSCs, chicken periosteal explants and growth plates of 6 weeks old mice. NF-κB/p65 activation was manipulated using pharmacological inhibitors, RNAi and activating agents. Gene expression and protein expression analysis, and (immuno)histochemical stainings were employed to determine the role of NF-κB/p65 in the Chondrogenic phase of endochondral development. Our data show that Chondrogenic Differentiation is facilitated by early transient activation of NF-κB/p65. NF-κB/p65-mediated signaling determines early expression of Sox9 and facilitates the subsequent Chondrogenic Differentiation programming by signaling through key Chondrogenic pathways. Conclusions/Significance The presented data demonstrate that NF-κB/p65 signaling, as well as its intensity and timing, represents one of the transcriptional regulatory mechanisms of the Chondrogenic developmental program of chondroprogenitor cells during endochondral ossification. Importantly, these results provide novel possibilities to improve the success of cartilage and bone regenerative techniques.

Bernhard Zabel - One of the best experts on this subject based on the ideXlab platform.

  • The antiviral protein viperin regulates Chondrogenic Differentiation via CXCL10 protein secretion.
    The Journal of biological chemistry, 2019
    Co-Authors: Mandy M. F. Steinbusch, Marjolein M. J. Caron, D.a. Surtel, Franziska Friedrich, Lodewijk W. Van Rhijn, Bernhard Zabel, Guus G. H. Van Den Akker, Paul Van Dijk, Mandy J. Peffers, Tim Jm Welting
    Abstract:

    Viperin (also known as radical SAM domain-containing 2 (RSAD2)) is an interferon-inducible and evolutionary conserved protein that participates in the cell's innate immune response against a number of viruses. Viperin mRNA is a substrate for endoribonucleolytic cleavage by RNase mitochondrial RNA processing (MRP) and mutations in the RNase MRP small nucleolar RNA (snoRNA) subunit of the RNase MRP complex cause cartilage-hair hypoplasia (CHH), a human developmental condition characterized by metaphyseal chondrodysplasia and severe dwarfism. It is unknown how CHH-pathogenic mutations in RNase MRP snoRNA interfere with skeletal development, and aberrant processing of RNase MRP substrate RNAs is thought to be involved. We hypothesized that viperin plays a role in Chondrogenic Differentiation. Using immunohistochemistry, real-time quantitative PCR, immunoblotting, ELISA, siRNA-mediated gene silencing, plasmid-mediated gene overexpression, label-free MS proteomics, and promoter reporter bioluminescence assays, we discovered here that viperin is expressed in differentiating chondrocytic cells and regulates their protein secretion and the outcome of Chondrogenic Differentiation by influencing transforming growth factor β (TGF-β)/SMAD family 2/3 (SMAD2/3) activity via C-X-C motif chemokine ligand 10 (CXCL10). Of note, we observed disturbances in this viperin-CXCL10-TGF-β/SMAD2/3 axis in CHH chondrocytic cells. Our results indicate that the antiviral protein viperin controls Chondrogenic Differentiation by influencing secretion of soluble proteins and identify a molecular route that may explain impaired Chondrogenic Differentiation of cells from individuals with CHH.

  • Expression of RMRP RNA is regulated in chondrocyte hypertrophy and determines Chondrogenic Differentiation.
    Scientific reports, 2017
    Co-Authors: Mandy M. F. Steinbusch, Marjolein M. J. Caron, D.a. Surtel, Franziska Friedrich, Ekkehart Lausch, Ger J. M. Pruijn, Wouter Verhesen, Blanche Schroen, Lodewijk W. Van Rhijn, Bernhard Zabel
    Abstract:

    Mutations in the RMRP-gene, encoding the lncRNA component of the RNase MRP complex, are the origin of cartilage-hair hypoplasia. Cartilage-hair hypoplasia is associated with severe dwarfism caused by impaired skeletal development. However, it is not clear why mutations in RMRP RNA lead to skeletal dysplasia. Since Chondrogenic Differentiation of the growth plate is required for development of long bones, we hypothesized that RMRP RNA plays a pivotal role in Chondrogenic Differentiation. Expression of Rmrp RNA and RNase MRP protein subunits was detected in the murine growth plate and during the course of Chondrogenic Differentiation of ATDC5 cultures, where Rmrp RNA expression was found to be correlated with chondrocyte hypertrophy. Genetic interference with Rmrp RNA expression in ATDC5 cultures caused a deregulation of Chondrogenic Differentiation, with a prominent impact on hypertrophy and changes in pre-rRNA processing and rRNA levels. Promoter reporter studies showed that Rmrp RNA expression responds to Chondrogenic morphogens. Chondrogenic trans-Differentiation of cartilage-hair hypoplasia fibroblasts was impaired with a pronounced impact on hypertrophic Differentiation. Together, our data show that RMRP RNA expression is regulated during different stages of Chondrogenic Differentiation and indicate that RMRP RNA may play a pivotal role in chondrocyte hypertrophy, with potential consequences for CHH pathobiology.