The role of Zfp467 in mediating the pro-osteogenic and anti-adipogenic effects on bone and bone marrow niche.
The role of Zfp467 in mediating the pro-osteogenic and anti-adipogenic effects on bone and bone marrow niche.
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DOI：
10.1016/j.bone.2020.115832
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发表时间：
2021-03
期刊：
影响因子：
4.1
通讯作者：
Rosen CJ
中科院分区：
文献类型：
--
作者：
Le PT;Liu H;Alabdulaaly L;Vegting Y;Calle IL;Gori F;Lanske B;Baron R;Rosen CJ
间充质祖细胞中PTH受体（Pth 1 r）的条件性缺失降低了成骨细胞分化和骨量，同时增强了脂肪生成和骨髓脂肪组织。从机制上讲，PTH抑制Zfp 467（一种前脂肪形成锌指转录因子）的表达。因此，间充质祖细胞中的Pth 1 r缺陷导致Zfp 467表达增加。基于这些观察结果，我们假设Zfp 467的遗传缺失将导致骨髓祖细胞命运向成骨和骨量增加的转变。为了验证这一假设，我们产生了Zfp 467 −/−小鼠。Zfp 467 −/−小鼠（−/−）明显小于Zfp 467 +/+小鼠（+/+）。μCT显示，−/−小鼠的骨小梁和皮质骨面积显著高于+/+小鼠，组织形态计量学显示，−/−小鼠的结构和动态形成参数高于+/+小鼠。在−/−小鼠中，包括Alpl、Sp 7和Acp 5在内的股骨基因表达增加，而在−/−小鼠中，脂联素、Cebpa、Lepr和Ppraγ mRNA较低。同样，在−/−小鼠中，腹股沟贮库中的Fabp 4和Lep也减少了。此外，在−/−与+/+小鼠中，骨髓脂肪细胞数量减少（p<0.007）。在体外，COB和BMSC-/-显示出更积极的ALP和茜素红染色和减少ORO液滴。Pth 1 r mRNA和蛋白质水平在来自−/−小鼠与+/+小鼠的COB和BMSC中增加（每个参数p<0.02，−/−与+/+）。与对照细胞相比，−/−细胞也表现出增强的内源性cAMP水平。此外，在卵巢切除（OVX）小鼠模型中，Zfp 467 −/−小鼠的脂肪量显著低于OVX +/+小鼠，但骨量相似。相比之下，在高脂饮食（HFD）小鼠模型中，除了外周和骨髓脂肪组织中脂肪细胞体积和脂肪生成相关基因表达减少外，在−/− HFD小鼠与+/+ HFD小鼠中还观察到成骨细胞数量和成骨相关基因表达增加。总之，这些结果表明ZFP 467负面影响骨骼稳态并有利于脂肪生成。Zfp 467的整体缺失增加了PTHR 1、cAMP和骨转换，因此其抑制是PTH信号传导及其调节的一个组成部分。这些数据支持Zfp 467在早期谱系分配中的关键作用，并提供了一种新的潜在机制，PTH通过该机制以合成代谢方式作用于骨重建单位。
Conditional deletion of the PTH receptor (Pth1r) in mesenchymal progenitors reduces osteoblast differentiation and bone mass while enhancing adipogenesis and bone marrow adipose tissue. Mechanistically, PTH suppresses the expression of Zfp467, a pro-adipogenic zinc finger transcription factor. Consequently, Pth1r deficiency in mesenchymal progenitors leads to increased Zfp467 expression. Based on these observations, we hypothesized that genetic loss of Zfp467 would lead to a shift in marrow progenitor cell fate towards osteogenesis and increased bone mass. To test this hypothesis, we generated Zfp467−/− mice. Zfp467−/− mice (−/−) were significantly smaller than Zfp467+/+ mice (+/+). μCT showed significantly higher trabecular bone and cortical bone area in −/− vs. +/+, and histomorphometry showed higher structural and dynamic formation parameters in −/− mice vs. +/+. Femoral gene expression including Alpl, Sp7, and Acp5 were increased in −/−mice, whereas Adiponectin, Cebpa, Lepr, and Ppraγ mRNA were lower in −/− mice. Similarly, Fabp4 and Lep in the inguinal depot were also decreased in −/− mice. Moreover, marrow adipocyte numbers were reduced in −/− vs +/+ mice (p<0.007). In vitro, COBs and BMSCs−/− showed more positive ALP and Alizarin Red staining and a decrease in ORO droplets. Pth1r mRNA and protein levels were increased in COBs and BMSCs from −/− mice vs +/+ (p<0.02 for each parameter, −/− vs. +/+). −/− cells also exhibited enhanced endogenous levels of cAMP vs. control cells. Moreover, in an ovariectomy (OVX) mouse model, Zfp467−/− mice had significantly lower fat mass but similar bone mass compared to OVX +/+ mice. In contrast, in a high fat diet (HFD) mouse model, in addition to reduced adipocyte volume and adipogenesis related gene expression in both peripheral and bone marrow fat tissue, greater osteoblast number and higher osteogenesis related gene expression were also observed in −/− HFD mice vs. +/+ HFD mice. Taken together, these results demonstrate that ZFP467 negatively influences skeletal homeostasis and favors adipogenesis. Global deletion of Zfp467 increases PTHR1, cAMP and bone turnover, hence its repression is a component of PTH signaling and its regulation. These data support a critical role for Zfp467 in early lineage allocation and provide a novel potential mechanism by which PTH acts in an anabolic manner on the bone remodeling unit.
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影响因子：
6.2
作者：
Kim, Sang Wan;Pajevic, Paola Divieti;Selig, Martin;Barry, Kevin J.;Yang, Jae-Yeon;Shin, Chan Soo;Baek, Wook-Young;Kim, Jung-Eun;Kronenberg, Henry M.
通讯作者：
Kronenberg, Henry M.
影响因子：
6.2
作者：
Beamer, Wesley G.;Shultz, Kathryn L.;Rosen, Clifford J.
通讯作者：
Rosen, Clifford J.
影响因子：
4.8
作者：
Ozkurt, IC;Pirih, FQ;Tetradis, S
通讯作者：
Tetradis, S
影响因子：
4.8
作者：
Li, Xin;Qin, Ling;Partridge, Nicola C.
通讯作者：
Partridge, Nicola C.
影响因子：
4.8
作者：
Kawai, Masanobu;Breggia, Anne C.;Rosen, Clifford J.
通讯作者：
Rosen, Clifford J.