Morc3 mutant mice exhibit reduced cortical area and thickness, accompanied by altered haematopoietic stem cells niche and bone cell differentiation

Gaurav Jadhav, Dian Teguh, Jacob Kenny, Jennifer Tickner, Jiake Xu

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    9 Citations (Scopus)

    Abstract

    Morc3, a member of a highly conserved nuclear matrix protein super-family plays an important part in chromatin remodeling, DNA repair, epigenetic regulation and cellular senescence. However, its role in bone homeostasis is not known. In the present study, a phenotype-driven ENU mouse mutagenesis screen revealed that Morc3mut+/- mice exhibit reduced cortical area and thickness with increased cortical porosity. Morc3mut+/- mice displayed reduced osteoclast numbers and surface per bone surface as well as osteocyte numbers, concomitant with altered gene expressions such as Rankl/Opg and Sost in ex vivo long bones. In vitro experiments revealed a significant increase in the number of Sca-1+/c-kit+ haematopoietic stem cells (HSCs), and a significant reduction in senescence associated â-galactosidase activity in bone marrow macrophages (BMMs). In addition, we observed a decrease in osteoclastogenesis and bone resorption accompanied by upregulation of STAT1 expression in osteoclast lineage cells. Strikingly, Morc3 protein localization within the nuclear membrane was shifted to the cytoplasm in Morc3mut+/- osteoclasts. Further, Morc3mut+/- mice displayed increased osteoblast differentiation and altered gene expression. Collectively, our data show that Morc3 is a previously unreported regulator of cortical bone homeostasis and haematopoietic stem cells niche, accompanied by altered bone cell differentiation.
    Original languageEnglish
    Article number25964
    Pages (from-to)1-13
    JournalScientific Reports
    Volume6
    DOIs
    Publication statusPublished - 18 May 2016

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    Stem Cell Niche
    Hematopoietic Stem Cells
    Cell Differentiation
    Osteoclasts
    Bone and Bones
    Homeostasis
    Nuclear Matrix-Associated Proteins
    Galactosidases
    Gene Expression
    Osteocytes
    Chromatin Assembly and Disassembly
    Cell Aging
    Porosity
    Nuclear Envelope
    Bone Resorption
    Osteoblasts
    Osteogenesis
    Epigenomics
    Mutagenesis
    DNA Repair

    Cite this

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    title = "Morc3 mutant mice exhibit reduced cortical area and thickness, accompanied by altered haematopoietic stem cells niche and bone cell differentiation",
    abstract = "Morc3, a member of a highly conserved nuclear matrix protein super-family plays an important part in chromatin remodeling, DNA repair, epigenetic regulation and cellular senescence. However, its role in bone homeostasis is not known. In the present study, a phenotype-driven ENU mouse mutagenesis screen revealed that Morc3mut+/- mice exhibit reduced cortical area and thickness with increased cortical porosity. Morc3mut+/- mice displayed reduced osteoclast numbers and surface per bone surface as well as osteocyte numbers, concomitant with altered gene expressions such as Rankl/Opg and Sost in ex vivo long bones. In vitro experiments revealed a significant increase in the number of Sca-1+/c-kit+ haematopoietic stem cells (HSCs), and a significant reduction in senescence associated {\^a}-galactosidase activity in bone marrow macrophages (BMMs). In addition, we observed a decrease in osteoclastogenesis and bone resorption accompanied by upregulation of STAT1 expression in osteoclast lineage cells. Strikingly, Morc3 protein localization within the nuclear membrane was shifted to the cytoplasm in Morc3mut+/- osteoclasts. Further, Morc3mut+/- mice displayed increased osteoblast differentiation and altered gene expression. Collectively, our data show that Morc3 is a previously unreported regulator of cortical bone homeostasis and haematopoietic stem cells niche, accompanied by altered bone cell differentiation.",
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    AU - Jadhav, Gaurav

    AU - Teguh, Dian

    AU - Kenny, Jacob

    AU - Tickner, Jennifer

    AU - Xu, Jiake

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    N2 - Morc3, a member of a highly conserved nuclear matrix protein super-family plays an important part in chromatin remodeling, DNA repair, epigenetic regulation and cellular senescence. However, its role in bone homeostasis is not known. In the present study, a phenotype-driven ENU mouse mutagenesis screen revealed that Morc3mut+/- mice exhibit reduced cortical area and thickness with increased cortical porosity. Morc3mut+/- mice displayed reduced osteoclast numbers and surface per bone surface as well as osteocyte numbers, concomitant with altered gene expressions such as Rankl/Opg and Sost in ex vivo long bones. In vitro experiments revealed a significant increase in the number of Sca-1+/c-kit+ haematopoietic stem cells (HSCs), and a significant reduction in senescence associated â-galactosidase activity in bone marrow macrophages (BMMs). In addition, we observed a decrease in osteoclastogenesis and bone resorption accompanied by upregulation of STAT1 expression in osteoclast lineage cells. Strikingly, Morc3 protein localization within the nuclear membrane was shifted to the cytoplasm in Morc3mut+/- osteoclasts. Further, Morc3mut+/- mice displayed increased osteoblast differentiation and altered gene expression. Collectively, our data show that Morc3 is a previously unreported regulator of cortical bone homeostasis and haematopoietic stem cells niche, accompanied by altered bone cell differentiation.

    AB - Morc3, a member of a highly conserved nuclear matrix protein super-family plays an important part in chromatin remodeling, DNA repair, epigenetic regulation and cellular senescence. However, its role in bone homeostasis is not known. In the present study, a phenotype-driven ENU mouse mutagenesis screen revealed that Morc3mut+/- mice exhibit reduced cortical area and thickness with increased cortical porosity. Morc3mut+/- mice displayed reduced osteoclast numbers and surface per bone surface as well as osteocyte numbers, concomitant with altered gene expressions such as Rankl/Opg and Sost in ex vivo long bones. In vitro experiments revealed a significant increase in the number of Sca-1+/c-kit+ haematopoietic stem cells (HSCs), and a significant reduction in senescence associated â-galactosidase activity in bone marrow macrophages (BMMs). In addition, we observed a decrease in osteoclastogenesis and bone resorption accompanied by upregulation of STAT1 expression in osteoclast lineage cells. Strikingly, Morc3 protein localization within the nuclear membrane was shifted to the cytoplasm in Morc3mut+/- osteoclasts. Further, Morc3mut+/- mice displayed increased osteoblast differentiation and altered gene expression. Collectively, our data show that Morc3 is a previously unreported regulator of cortical bone homeostasis and haematopoietic stem cells niche, accompanied by altered bone cell differentiation.

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