title: Maf promotes osteoblast differentiation in mice by mediating the age-related switch in mesenchymal cell differentiation.
abstract: Aging leads to the disruption of the homeostatic balance of multiple biological systems. In bone marrow multipotent mesenchymal cells undergo differentiation into various anchorage-dependent cell types, including osteoblasts and adipocytes. With age as well as with treatment of antidiabetic drugs such as thiazolidinediones, mesenchymal cells favor differentiation into adipocytes, resulting in an increased number of adipocytes and a decreased number of osteoblasts, causing osteoporosis. The mechanism behind this differentiation switch is unknown. Here we show an age-related decrease in the expression of Maf in mouse mesenchymal cells, which regulated mesenchymal cell bifurcation into osteoblasts and adipocytes by cooperating with the osteogenic transcription factor Runx2 and inhibiting the expression of the adipogenic transcription factor Pparg. The crucial role of Maf in both osteogenesis and adipogenesis was underscored by in vivo observations of delayed bone formation in perinatal Maf(-/-) mice and an accelerated formation of fatty marrow associated with bone loss in aged Maf(+/-) mice. This study identifies a transcriptional mechanism for an age-related switch in cell fate determination and may provide a molecular basis for novel therapeutic strategies against age-related bone diseases.
authors.affiliation: Department of Cell Signaling, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan.
authors.forename: Keizo
authors.initials: K
authors.lastname: Nishikawa
authors.forename: Tomoki
authors.initials: T
authors.lastname: Nakashima
authors.forename: Shu
authors.initials: S
authors.lastname: Takeda
authors.forename: Masashi
authors.initials: M
authors.lastname: Isogai
authors.forename: Michito
authors.initials: M
authors.lastname: Hamada
authors.forename: Ayako
authors.initials: A
authors.lastname: Kimura
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Kodama
authors.forename: Akira
authors.initials: A
authors.lastname: Yamaguchi
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Owen
authors.forename: Satoru
authors.initials: S
authors.lastname: Takahashi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takayanagi
mesh_terms: D050156:Adipogenesis; D000375:Aging; D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage; D002478:Cells, Cultured; D050659:Core Binding Factor Alpha 1 Subunit / Q000032:analysis; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010006:Osteoblasts / Q000166:cytology*; D010012:Osteogenesis; D010024:Osteoporosis / Q000209:etiology / Q000628:therapy; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000235:genetics; D051257:Proto-Oncogene Proteins c-maf / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; C495608:Maf protein, mouse; D047495:PPAR gamma; D051257:Proto-Oncogene Proteins c-maf; D017382:Reactive Oxygen Species; C493716:Runx2 protein, mouse; D016159:Tumor Suppressor Protein p53