Loss of Notch signaling in skeletal stem cells enhances bone formation with aging

查看全文 作　　者：Lindsey [1]H.Remark;Kevin [1]Leclerc;Malissa [1]Ramsukh;Ziyan [2]Lin;Sooyeon [1,3]Lee;Backialakshmi [4]Dharmalingam;Lauren [1]Gillinov;Vasudev [5]V.Nayak;Paulo El [1]Parente;Margaux [1]Sambon;Pablo [1]J.Atria;Mohamed [6]A.E.Ali;Lukasz [7,8,9]Witek;Alesha [1]B.Castillo;Christopher [6]Y.Park;Ralf [4]H.Adams;Aristotelis [2]Tsirigos;Sophie [1]M.Morgani;Philipp [1,10]Leucht

机构地区：[1]Department of Orthopaedic Surgery,NYU Robert I.Grossman School of Medicine,New York,NY,USA;[2]Applied Bioinformatics Laboratories,NYU Grossman School of Medicine,New York,NY,USA;[3]Institute of Comparative Molecular Endocrinology,Ulm University,Ulm,Germany;[4]Max Planck Institute for Molecular Biomedicine,Department of Tissue Morphogenesis,and University of Münster,Faculty of Medicine,D-48149 Münster,Germany;[5]Department of Biochemistry and Molecular Biology,University of Miami Miller School of Medicine,Miami,FL,USA;[6]Department of Pathology,NYU Robert I.Grossman School of Medicine,New York,NY,USA;[7]Biomaterials Division,New York University College of Dentistry,New York,NY,USA;[8]Hansjörg Wyss Department of Plastic Surgery,NYU Grossman School of Medicine,New York University,New York,NY,USA;[9]Department of Biomedical Engineering,Tandon School of Engineering,New York University,Brooklyn,NY,USA;[10]Department of Cell Biology,NYU Robert I.Grossman School of Medicine,New York,NY,USA

出　　处：《Bone Research》索引2023年第11卷第4期,共14页

基　　金：supported by a K08AR069099 (P.L.) from the National Institutes of Health/ National Institute of Arthritis and Musculoskeletal and Skin;supported by an R01AG056169 and a gift by the Patricia and Frank Zarb Family;supported by an F30AG072834 from the National Institutes of Health/National Institute on Aging;funded through NIH Grant S10OD010751 and the Preclinical Imaging Laboratory;partially supported by the Laura and Isaac Perlmutter Cancer Center Support Grant NIH/NCI 5P30CA016087;NIBIB Biomedical Technology Resource Center Grant NIH P41 EB017183;supported in part by grant P30CA016087 from the National Institutes of Health/National Cancer Institute;partially supported by the Cancer Center Support Grant P30CA016087 at the Laura and Isaac Perlmutter Cancer Center。 摘　　要：Skeletal stem and progenitor cells(SSPCs) perform bone maintenance and repair. With age, they produce fewer osteoblasts and more adipocytes leading to a loss of skeletal integrity. The molecular mechanisms that underlie this detrimental transformation are largely unknown. Single-cell RNA sequencing revealed that Notch signaling becomes elevated in SSPCs during aging. To examine the role of increased Notch activity, we deleted Nicastrin, an essential Notch pathway component, in SSPCs in vivo. Middle-aged conditional knockout mice displayed elevated SSPC osteo-lineage gene expression, increased trabecular bone mass, reduced bone marrow adiposity, and enhanced bone repair. Thus, Notch regulates SSPC cell fate decisions, and moderating Notch signaling ameliorates the skeletal aging phenotype, increasing bone mass even beyond that of young mice. Finally, we identified the transcription factor Ebf3 as a downstream mediator of Notch signaling in SSPCs that is dysregulated with aging, highlighting it as a promising therapeutic target to rejuvenate the aged skeleton. 关键词：NOTCH SKELETAL ELEVATED

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Loss of Notch signaling in skeletal stem cells enhances bone formation with aging

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