Maf promotes osteoblast differentiation in mice by mediating the age-related switch in mesenchymal cell differentiation
Maf promotes osteoblast differentiation in mice by mediating the age-related switch in mesenchymal cell differentiation
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DOI：
10.1172/jci42528
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发表时间：
2010-10-01
影响因子：
15.9
通讯作者：
Takayanagi, Hiroshi
中科院分区：
文献类型：
--
作者：
Nishikawa, Keizo;Nakashima, Tomoki;Takayanagi, Hiroshi
衰老导致多种生物系统的动态平衡被破坏。在骨髓中，多能间充质细胞可以分化为各种依赖于锚定的细胞类型，包括成骨细胞和脂肪细胞。随着年龄的增长以及抗糖尿病药物如噻唑烷二酮类药物的治疗，间充质细胞有利于分化为脂肪细胞，导致脂肪细胞数量增加和成骨细胞数量减少，从而导致骨质疏松。这种分化开关背后的机制尚不清楚。在这里，我们发现MAF在小鼠间充质细胞中的表达随着年龄的增长而降低，它通过与成骨转录因子Runx2协同作用和抑制成脂转录因子PPARG的表达来调节间充质细胞向成骨细胞和脂肪细胞的分叉。围产期MAF(-/-)小鼠延迟骨形成的体内观察以及老年MAF(+/-)小鼠脂肪骨髓的加速形成与骨丢失相关，强调了MAF在成骨和成脂中的关键作用。这项研究确定了决定细胞命运的年龄相关开关的转录机制，并可能为抗年龄相关骨骼疾病的新治疗策略提供分子基础。
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.