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      Deficiency of the SMOC2 matricellular protein impairs bone healing and produces age-dependent bone loss

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          Abstract

          Secreted extracellular matrix components which regulate craniofacial development could be reactivated and play roles in adult wound healing. We report a patient with a loss-of-function of the secreted matricellular protein SMOC2 (SPARC related modular calcium binding 2) presenting severe oligodontia, microdontia, tooth root deficiencies, alveolar bone hypoplasia, and a range of skeletal malformations. Turning to a mouse model, Smoc2-GFP reporter expression indicates SMOC2 dynamically marks a range of dental and bone progenitors. While germline Smoc2 homozygous mutants are viable, tooth number anomalies, reduced tooth size, altered enamel prism patterning, and spontaneous age-induced periodontal bone and root loss are observed in this mouse model. Whole-genome RNA-sequencing analysis of embryonic day (E) 14.5 cap stage molars revealed reductions in early expressed enamel matrix components ( Odontogenic ameloblast-associated protein) and dentin dysplasia targets ( Dentin matrix acidic phosphoprotein 1). We tested if like other matricellular proteins SMOC2 was required for regenerative repair. We found that the Smoc2-GFP reporter was reactivated in adjacent periodontal tissues 4 days after tooth avulsion injury. Following maxillary tooth injury, Smoc2 −/− mutants had increased osteoclast activity and bone resorption surrounding the extracted molar. Interestingly, a 10-day treatment with the cyclooxygenase 2 (COX2) inhibitor ibuprofen (30 mg/kg body weight) blocked tooth injury-induced bone loss in Smoc2 −/− mutants, reducing matrix metalloprotease (Mmp)9. Collectively, our results indicate that endogenous SMOC2 blocks injury-induced jaw bone osteonecrosis and offsets age-induced periodontal decay.

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          Most cited references43

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          Functions of RANKL/RANK/OPG in bone modeling and remodeling.

          The discovery of the RANKL/RANK/OPG system in the mid 1990s for the regulation of bone resorption has led to major advances in our understanding of how bone modeling and remodeling are regulated. It had been known for many years before this discovery that osteoblastic stromal cells regulated osteoclast formation, but it had not been anticipated that they would do this through expression of members of the TNF superfamily: receptor activator of NF-kappaB ligand (RANKL) and osteoprotegerin (OPG), or that these cytokines and signaling through receptor activator of NF-kappaB (RANK) would have extensive functions beyond regulation of bone remodeling. RANKL/RANK signaling regulates osteoclast formation, activation and survival in normal bone modeling and remodeling and in a variety of pathologic conditions characterized by increased bone turnover. OPG protects bone from excessive resorption by binding to RANKL and preventing it from binding to RANK. Thus, the relative concentration of RANKL and OPG in bone is a major determinant of bone mass and strength. Here, we review our current understanding of the role of the RANKL/RANK/OPG system in bone modeling and remodeling.
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            The Lgr5 intestinal stem cell signature: robust expression of proposed quiescent '+4' cell markers.

            Two types of stem cells are currently defined in small intestinal crypts: cycling crypt base columnar (CBC) cells and quiescent '+4' cells. Here, we combine transcriptomics with proteomics to define a definitive molecular signature for Lgr5(+) CBC cells. Transcriptional profiling of FACS-sorted Lgr5(+) stem cells and their daughters using two microarray platforms revealed an mRNA stem cell signature of 384 unique genes. Quantitative mass spectrometry on the same cell populations identified 278 proteins enriched in intestinal stem cells. The mRNA and protein data sets showed a high level of correlation and a combined signature of 510 stem cell-enriched genes was defined. Spatial expression patterns were further characterized by mRNA in-situ hybridization, revealing that approximately half of the genes were expressed in a gradient with highest levels at the crypt bottom, while the other half was expressed uniquely in Lgr5(+)stem cells. Lineage tracing using a newly established knock-in mouse for one of the signature genes, Smoc2, confirmed its stem cell specificity. Using this resource, we find-and confirm by independent approaches-that the proposed quiescent/'+4' stem cell markers Bmi1, Tert, Hopx and Lrig1 are robustly expressed in CBC cells.
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              A cre-transgenic mouse strain for the ubiquitous deletion of loxP-flanked gene segments including deletion in germ cells.

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                Author and article information

                Contributors
                agnes.bloch-zupan@unistra.fr
                karennied1@gmail.com
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                9 September 2020
                9 September 2020
                2020
                : 10
                Affiliations
                [1 ]GRID grid.420255.4, ISNI 0000 0004 0638 2716, Developmental Biology and Stem Cells Department, , Institute of Genetics and of Molecular and Cellular Biology (IGBMC), ; 1 rue Laurent Fries, BP 10142, 67404 Illkirch, France
                [2 ]GRID grid.4444.0, ISNI 0000 0001 2112 9282, Centre National de la Recherche Scientifique, UMR7104, ; Illkirch, France
                [3 ]GRID grid.457373.1, Institut National de la Santé et de la Recherche Médicale, INSERM U1258, ; Illkirch, France
                [4 ]GRID grid.11843.3f, ISNI 0000 0001 2157 9291, Université de Strasbourg, ; Illkirch, France
                [5 ]GRID grid.9786.0, ISNI 0000 0004 0470 0856, Faculty of Dentistry, Pediatrics Division, Preventive Department, , Khon Kaen University, ; Khon Kaen, Thailand
                [6 ]GRID grid.11843.3f, ISNI 0000 0001 2157 9291, Faculté de Chirurgie Dentaire, , Université de Strasbourg, ; 8 rue Ste Elisabeth, 67000 Strasbourg, France
                [7 ]GRID grid.412220.7, ISNI 0000 0001 2177 138X, Hôpitaux Universitaires de Strasbourg, Pôle de Médecine et Chirurgie Bucco-Dentaires, Centre de Référence des Maladies Rares Orales et Dentaires, CRMR O Rares, Filière TETECOU, ERN CRANIO, ; 1 place de l’Hôpital, 67000 Strasbourg, France
                [8 ]GRID grid.412220.7, ISNI 0000 0001 2177 138X, Regenerative NanoMedicine, INSERM UMR1260, FMTS, Hôpitaux Universitaires de Strasbourg, ; 11 rue Humann, 67000 Strasbourg, France
                [9 ]GRID grid.11843.3f, ISNI 0000 0001 2157 9291, Biomaterials and Bioengineering, , Université de Strasbourg, INSERM UMR1121, ; 11 rue Humann, 67000 Strasbourg, France
                [10 ]Hubrecht Institute, University Medical Center Utrecht, and University Utrecht, Utrecht, The Netherlands
                [11 ]GRID grid.11843.3f, ISNI 0000 0001 2157 9291, Faculté de Médecine, , Université de Strasbourg, ; FMTS, 4 Rue Kirschleger, 67000 Strasbourg, France
                [12 ]GRID grid.83440.3b, ISNI 0000000121901201, Eastman Dental Institute, , University College London, ; London, UK
                Article
                71749
                10.1038/s41598-020-71749-6
                7481257
                84b2ef13-c973-4c42-bcfd-ae2789145db9
                © The Author(s) 2020

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                Funding
                Funded by: Institut d'Etudes Avancées (Institute of Advanced Studies) de l'Université de Strasbourg (USIAS Fellows 2015)
                Funded by: INTERREG IV and INTERREG V Nr.1.7 RARENET, Institute of Advanced Studies of Strasbourg University (USIAS)
                Funded by: EU-funded projects (ERDF) A27 “Oro-dental manifestations of rare diseases” in the framework of the RMT-TMO Offensive Sciences initiative INTERREG IV and INTERREG V Nr.1.7 RARENET
                Categories
                Article
                Custom metadata
                © The Author(s) 2020

                Uncategorized
                development,dental diseases,bone
                Uncategorized
                development, dental diseases, bone

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