Stability of mRNA influences steoporotic bone mass via CNOT3
Stability of mRNA influences steoporotic bone mass via CNOT3
复制标题
mRNA 的稳定性通过 CNOT3 影响骨质疏松骨量
DOI：
10.1073/pnas.1316932111
复制
发表时间：
2014
期刊：
影响因子：
--
通讯作者：
M. Yamamoto T. (13名)
中科院分区：
文献类型：
--
作者：
Watanabe;C. Morita;M. Yamamoto T. (13名)
破骨细胞的发生受转录后和转录事件的控制。然而，破骨细胞生成的转录后调控机制还不完全清楚。hocT 3是调节mRNA稳定性的CCR 4家族的一个组成部分，但其在骨中的功能尚不清楚。在此，我们发现Cnot 3基因缺失可导致骨质疏松症，Cnot 3基因缺失可导致骨吸收增强和骨形成增加，从而导致高转换型骨丢失。在细胞水平上，Cnot 3缺陷增强了NF-κB配体受体激活因子（RANKL）以细胞自主方式对破骨细胞生成的作用。相反，Cnot 3缺陷并不直接影响成骨细胞; Cnot 3缺陷并不改变RANKL的表达，但增强了体内骨中NF-κB受体激活因子（RANK）mRNA的表达; Cnot 3缺陷可使小鼠骨髓细胞中RANK mRNA的稳定性提高约2倍; Cnot 3敲低也可增加破骨细胞前体细胞系中RANK mRNA的表达。抗hocT 3抗体免疫沉淀RANK mRNA。Cnot 3缺陷稳定了与RANK mRNA 3′-UTR片段连接的荧光素酶报告基因表达。相反，Cnot 3过表达使与RANK 3′-UTR连接的荧光素酶报告基因不稳定。在表现出严重骨质疏松症的老年小鼠中，骨中的Cnot 3表达水平在体内降低约三倍。令人惊讶的是，这些老年小鼠中的Cnot 3缺乏进一步加剧了骨质疏松症，这也是通过增强骨细胞活性而发生的。我们的研究结果表明，hocT 3是一个关键的调节骨量作用于骨吸收，通过转录后下调RANK mRNA的稳定性，至少部分，即使在衰老诱导的骨质疏松症。
Osteoclastogenesis is under the control of posttranscriptional and transcriptional events. However, posttranscriptional regulation of osteoclastogenesis is incompletely understood. CNOT3 is a component of the CCR4 family that regulates mRNA stability, but its function in bone is not known. Here, we show thatCnot3deficiency by deletion of a single allele induces osteoporosis.Cnot3deficiency causes an enhancement in bone resorption in association with an elevation in bone formation, resulting in high-turnover type bone loss. At the cellular level,Cnot3deficiency enhances receptor activator of NF-κB ligand (RANKL) effects on osteoclastogenesis in a cell-autonomous manner. Conversely,Cnot3deficiency does not affect osteoblasts directly.Cnot3deficiency does not alter RANKL expression but enhances receptor activator of NF-κB (RANK) mRNA expression in bone in vivo.Cnot3deficiency promotes RANK mRNA stability about twofold in bone marrow cells of mice.Cnot3knockdown also increases RANK mRNA expression in the precursor cell line for osteoclasts. Anti-CNOT3 antibody immunoprecipitates RANK mRNA.Cnot3deficiency stabilizes luciferase reporter expression linked to the 3′-UTR fragment of RANK mRNA. In contrast,Cnot3overexpression destabilizes the luciferase reporter linked to RANK 3′-UTR. In aged mice that exhibit severe osteoporosis,Cnot3expression levels in bone are reduced about threefold in vivo. Surprisingly,Cnot3deficiency in these aged mice further exacerbates osteoporosis, which also occurs via enhancement of osteoclastic activity. Our results reveal that CNOT3 is a critical regulator of bone mass acting on bone resorption through posttranscriptional down-regulation of RANK mRNA stability, at least in part, even in aging-induced osteoporosis.