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Maf promotes osteoblast differentiation in mice by mediating the age-related switch in mesenchymal cell differentiation
Keizo Nishikawa, … , Satoru Takahashi, Hiroshi Takayanagi
Keizo Nishikawa, … , Satoru Takahashi, Hiroshi Takayanagi
Published September 27, 2010
Citation Information: J Clin Invest. 2010;120(10):3455-3465. https://doi.org/10.1172/JCI42528.
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Maf promotes osteoblast differentiation in mice by mediating the age-related switch in mesenchymal cell differentiation

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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

Keizo Nishikawa, Tomoki Nakashima, Shu Takeda, Masashi Isogai, Michito Hamada, Ayako Kimura, Tatsuhiko Kodama, Akira Yamaguchi, Michael J. Owen, Satoru Takahashi, Hiroshi Takayanagi

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Figure 1

Impaired bone formation in Maf–/– mice.

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Impaired bone formation in Maf–/– mice.
   
(A) A genome-wide screening ...
(A) A genome-wide screening of transcription factor mRNAs during in vitro differentiation of osteoblasts (OBs) and a comparison of their expression between 8- and 32-week-old BMSCs. The increase in Maf expression during osteoblastogenesis was confirmed in calvarial osteoblasts (RNA blot analysis, right top). Maf expression was markedly lower in BMSCs derived from the aged mice (real-time RT-PCR analysis, right bottom). Screening results are summarized in the Venn diagram. *P < 0.05; **P < 0.01. (B) Alizarin red/alcian blue staining of E17 embryos (top). Top view of calvaria (bottom). Images in B are composites. (C) Histology (von Kossa staining) and microcomputed tomography analysis of WT and Maf–/– littermates at P0 (n = 3). Scale bar: 100 μm. (D) ALP and von Kossa staining of osteogenic fronts (OFs) in the calvaria of WT and Maf–/– littermates. Scale bar: 100 μm. (E) Expression of Bglap1 in the calvaria of WT and Maf–/– mice (in situ hybridization). Scale bar: 100 μm.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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