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 β-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.
Highlights
Morc[3] (NXP2/KIAA0136/ZCWCC3) is a member of a highly conserved nuclear protein super-family, with characteristic domains that directly link the Morc proteins to signaling-dependent chromatin remodeling and epigenetic regulation[3]
Micro computed tomography analysis revealed that the cortical bone mass and cortical BMD were significantly lower in young Morc3mut +/− mice compared to age- and sex-matched wild type (WT) littermates (Fig. 1B–K), and these differences persisted in older mutant mice (Supplementary Fig. 2), suggesting defects in cortical bone growth
We found a significant increase in the number of putative haematopoietic stem cells (HSCs) (Sca-1+/c-kit+) in the Morc3mut +/− bone marrow (Fig. 3D), but no changes in the proportion of triple negative (CD11blow/−/CD3−/B220−) osteoclast progenitors (Fig. 3B), or putative mesenchymal stem cells (MSCs) (Sca-1+/c-kit−) (Fig. 3E)
Summary
Morc[3] (NXP2/KIAA0136/ZCWCC3) is a member of a highly conserved nuclear protein super-family, with characteristic domains that directly link the Morc proteins to signaling-dependent chromatin remodeling and epigenetic regulation[3]. Morc[3] plays an important role in p53 induced cellular senescence by activating p53 and localizing it to PML nuclear bodies[8]. It binds to PML through small ubiquitin-like modifier (SUMO) and SUMO-interacting motif (SIM). ROR1 co-operates with the pre-B cell receptor through activation of downstream signaling pathways such as AKT and MAPK to promote survival of acute lymphoblastic leukemia[11] This suggests that Morc[3] is associated with the regulation of cell signaling pathways that control cell survival and proliferation. Morc[3] is a transcriptional regulator of proteins involved in signal transduction pathways (IFN-activated STAT, AKT and MAPK) and calcium homeostasis. We uncovered that Morc[3] mutant mice exhibit reduced cortical area and thickness with increased cortical porosity, accompanied by altered haematopoietic stem cells niche and bone cell differentiation, as well as by the upregulation of IFN-βand STAT1 expression in osteoclast and osteoblast lineage cells
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