The GDF11-FTO-PPARγ axis controls the shift of osteoporotic MSC fate to adipocyte and inhibits bone formation during osteoporosis
The GDF11-FTO-PPARγ axis controls the shift of osteoporotic MSC fate to adipocyte and inhibits bone formation during osteoporosis
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DOI：
10.1016/j.bbadis.2018.09.015
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发表时间：
2018-12-01
影响因子：
6.2
通讯作者：
Xu, You-Jia
中科院分区：
文献类型：
--
作者：
Shen, Guang-Si;Zhou, Hai-Bin;Xu, You-Jia
在骨质疏松症中，骨间充质干细胞（BMSC）谱系向脂肪细胞的转变导致骨量和脂肪之间的不平衡，从而增加骨折的风险。这一过程背后的机制尚不完全清楚。脂肪质量和肥胖相关蛋白（Fat mass and obesity associated protein， FTO）是一种RNA去甲基化酶，可使各种甲基化的核酸去甲基化，参与各种生理和病理过程。在这里，我们确定FTO是骨质疏松症期间BMSC命运决定的调节因子。在人类和小鼠衰老或骨质疏松期间，FTO通过GDF11（生长分化因子11）-C/EBP依赖机制在骨髓中上调。FTO在骨髓间充质干细胞的脂肪细胞分化过程中表达上调，而在成骨细胞分化过程中表达下调。功能获得和功能丧失实验表明，FTO有利于骨髓间充质干细胞向脂肪细胞而非成骨细胞分化。进一步的机制研究表明，FTO结合并去甲基化了过氧化物酶体增殖体激活受体γ (Pparg)的mRNA，导致Pparg mRNA表达增加。相反，Pparg敲低抑制GDF11-FTO在骨髓间充质干细胞成骨分化过程中的功能。此外，成骨细胞中Fto的条件性基因敲除可以抑制小鼠骨质减少的发生。总之，我们的研究结果表明，GDF11-FTO-Pparg轴促进骨质疏松的BMSC向脂肪细胞的转变，并抑制骨质疏松期间的骨形成。
During osteoporosis, the shift of bone mesenchymal stem cell (BMSC) lineage commitment to adipocyte leads to the imbalance between bone mass and fat, which increases the risk of fracture. The mechanism underlying this process is not fully understood. Fat mass and obesity-associated protein (FTO) is an RNA demethylase that demethylates various methylated nucleic acids and participates in various physiological and pathological processes. Here we identified FTO as a regulator for BMSC fate determination during osteoporosis. FTO was up regulated in bone marrow during aging or osteoporosis in human and mice in a GDF11(growth differentiation factor 11)-C/EBP alpha-dependent mechanism. The expression of FTO was also up-regulated during adipocyte differentiation of BMSCs whereas its expression was down-regulated during osteoblast differentiation. Gain-of function and loss-of-function experiments showed that FTO favored the BMSCs to differentiate to adipocytes rather than osteoblasts. Further mechanism study demonstrated that FTO bound and demethylated the mRNA of the Peroxisome proliferator-activated receptor gamma (Pparg), leading to the increase in the expression of Pparg mRNA. Reversely, Pparg knockdown blocked the function of GDF11-FTO during osteoblast differentiation of BMSCs. Furthermore, conditionally genetic knockout of Fto in osteoblasts inhibited the development of osteopenia in mice. Collectively, our findings demonstrated that GDF11-FTO-Pparg axis promoted the shift of osteoporotic BMSC fate to adipocyte and inhibited bone formation during osteoporosis.