Maf promotes osteoblast differentiation in mice by mediating the age-related switch in mesenchymal cell differentiation.
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.
Nishikawa
Keizo
K
Department of Cell Signaling, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan.
Nakashima
Tomoki
T
Takeda
Shu
S
Isogai
Masashi
M
Hamada
Michito
M
Kimura
Ayako
A
Kodama
Tatsuhiko
T
Yamaguchi
Akira
A
Owen
Michael J
MJ
Takahashi
Satoru
S
Takayanagi
Hiroshi
H
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
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