Negative feedback loop of bone resorption by NFATc1-dependent induction of Cadm1.
Negative feedback loop of bone resorption by NFATc1-dependent induction of Cadm1.
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DOI：
10.1371/journal.pone.0175632
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Tanaka S
中科院分区：
文献类型：
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作者：
Nakamura S;Koyama T;Izawa N;Nomura S;Fujita T;Omata Y;Minami T;Matsumoto M;Nakamura M;Fujita-Jimbo E;Momoi T;Miyamoto T;Aburatani H;Tanaka S
组蛋白H3赖氨酸4和赖氨酸27 （H3K4me3和H3K27me3）在基因启动子区域的三甲基化对基因表达具有关键调控作用。关键发育基因往往表现出组蛋白修饰模式的变化，从H3K4me3/H3K27me3二价模式到H3K4me3单价模式。通过对骨髓源性巨噬细胞（BMMs）和成熟破骨细胞进行全面的染色质免疫沉淀和测序，我们发现细胞表面粘附分子1 （Cadm1）是活化T细胞核因子1 （NFATc1）的直接靶标，并且在BMMs中表现为二价组蛋白模式，而在破骨细胞中表现为单价模式。核因子κ B配体受体激活剂（RANKL）上调Cadm1在BMMs中的表达，并被钙调磷酸酶/NFATc1抑制剂FK506阻断。与野生型小鼠相比，cadm1缺陷小鼠的骨量明显减少，这是由于cadm1缺陷破骨细胞的分化、存活和骨吸收活性增加。这些结果表明，Cadm1是RANKL通过表观遗传修饰诱导的NFATc1的直接靶点，并以负反馈的方式调节破骨细胞骨吸收。
Trimethylation of histone H3 lysine 4 and lysine 27 (H3K4me3 and H3K27me3) at gene promoter regions critically regulates gene expression. Key developmental genes tend to exhibit changes in histone modification patterns from the H3K4me3/H3K27me3 bivalent pattern to the H3K4me3 monovalent pattern. Using comprehensive chromatin immunoprecipitation followed by sequencing in bone marrow-derived macrophages (BMMs) and mature osteoclasts, we found that cell surface adhesion molecule 1 (Cadm1) is a direct target of nuclear factor of activated T cells 1 (NFATc1) and exhibits a bivalent histone pattern in BMMs and a monovalent pattern in osteoclasts. Cadm1 expression was upregulated in BMMs by receptor activator of nuclear factor kappa B ligand (RANKL), and blocked by a calcineurin/NFATc1 inhibitor, FK506. Cadm1-deficient mice exhibited significantly reduced bone mass compared with wild-type mice, which was due to the increased osteoclast differentiation, survival and bone-resorbing activity in Cadm1-deficient osteoclasts. These results suggest that Cadm1 is a direct target of NFATc1, which is induced by RANKL through epigenetic modification, and regulates osteoclastic bone resorption in a negative feedback manner.