title: Maintenance of Bone Homeostasis by DLL1-Mediated Notch Signaling.
abstract: Adult bone mass is maintained through a balance of the activities of osteoblasts and osteoclasts. Although Notch signaling has been shown to maintain bone homeostasis by controlling the commitment, differentiation, and function of cells in both the osteoblast and osteoclast lineages, the precise mechanisms by which Notch performs such diverse and complex roles in bone physiology remain unclear. By using a transgenic approach that modified the expression of delta-like 1 (DLL1) or Jagged1 (JAG1) in an osteoblast-specific manner, we investigated the ligand-specific effects of Notch signaling in bone homeostasis. This study demonstrated for the first time that the proper regulation of DLL1 expression, but not JAG1 expression, in osteoblasts is essential for the maintenance of bone remodeling. DLL1-induced Notch signaling was responsible for the expansion of the bone-forming cell pool by promoting the proliferation of committed but immature osteoblasts. However, DLL1-Notch signaling inhibited further differentiation of the expanded osteoblasts to become fully matured functional osteoblasts, thereby substantially decreasing bone formation. Osteoblast-specific expression of DLL1 did not alter the intrinsic differentiation ability of cells of the osteoclast lineage. However, maturational arrest of osteoblasts caused by the DLL1 transgene impaired the maturation and function of osteoclasts due to a failed osteoblast-osteoclast coupling, resulting in severe suppression of bone metabolic turnover. Taken together, DLL1-mediated Notch signaling is critical for proper bone remodeling as it regulates the differentiation and function of both osteoblasts and osteoclasts. Our study elucidates the importance of ligand-specific activation of Notch signaling in the maintenance of bone homeostasis. J. Cell. Physiol. 232: 2569-2580, 2017. © 2016 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals Inc.
authors.affiliation: Center for Regenerative Medicine, Tokai University School of Medicine, Isehara, Japan.|Department of Hematology-Oncology, Tokai University School of Medicine, Isehara, Japan.
authors.forename: Yukari
authors.initials: Y
authors.lastname: Muguruma
authors.affiliation: Department of Immunology, Tokai University School of Medicine, Isehara, Japan.
authors.forename: Katsuto
authors.initials: K
authors.lastname: Hozumi
authors.affiliation: Center for Regenerative Medicine, Tokai University School of Medicine, Isehara, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Warita
authors.affiliation: Center for Regenerative Medicine, Tokai University School of Medicine, Isehara, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Yahata
authors.affiliation: Center for Regenerative Medicine, Tokai University School of Medicine, Isehara, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Uno
authors.affiliation: Central Institute for Experimental Animals, Kawasaki, Japan.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Ito
authors.affiliation: Center for Regenerative Medicine, Tokai University School of Medicine, Isehara, Japan.|Department of Hematology-Oncology, Tokai University School of Medicine, Isehara, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Ando
mesh_terms: D000818:Animals; D016723:Bone Remodeling; D001862:Bone Resorption / Q000235:genetics / Q000378:metabolism; D002135:Calcium-Binding Proteins; D002454:Cell Differentiation; D019070:Cell Lineage; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D005269:Femur / Q000196:embryology / Q000254:growth & development / Q000378:metabolism*; D005838:Genotype; D005865:Gestational Age; D006706:Homeostasis; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D000072100:Jagged-1 Protein / Q000235:genetics / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000378:metabolism*; D010010:Osteoclasts / Q000378:metabolism; D010012:Osteogenesis; D010641:Phenotype; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction; D013234:Stem Cells / Q000378:metabolism*; D013977:Tibia / Q000196:embryology / Q000254:growth & development / Q000378:metabolism*
chemical_list: D002135:Calcium-Binding Proteins; C512941:DLK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D051880:Receptors, Notch