miR-21 deficiency inhibits osteoclast function and prevents bone loss in mice.
miR-21 deficiency inhibits osteoclast function and prevents bone loss in mice.
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miR-21缺陷抑制破骨细胞功能并防止小鼠骨质流失
DOI：
10.1038/srep43191
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发表时间：
2017-02-27
影响因子：
4.6
通讯作者：
Jin Y
中科院分区：
文献类型：
--
作者：
Hu CH;Sui BD;Du FY;Shuai Y;Zheng CX;Zhao P;Yu XR;Jin Y
microRNA是骨代谢中的关键转录后调节因子。我们之前已经在体外证实了miR-21促进骨生成，同时研究也揭示了miR-21在体外作为破骨细胞生成的调节剂和破骨细胞分化的促进剂。然而，体内数据仍然缺乏识别miR-21的骨骼功能，特别是其对骨质疏松症的影响。在这里，使用miR-21敲除（miR-21−/−）小鼠，我们研究了miR-21对骨发育，骨重建和骨丢失的影响。出乎意料的是，miR-21−/−小鼠在发育中表现出正常的骨骼表型，并在体内维持成骨细胞生成。此外，通过靶向Sprouty 1（Spry 1）的miR-21，miR-21-/-小鼠显示核因子κB配体受体激活剂（RANKL）增加，骨保护素（OPG）减少。然而，有趣的是，miR-21缺乏在生理上促进了骨小梁质量的增加。此外，在病理状态下，对骨量的保护在miR-21−/−小鼠中很突出。这些骨骼效应归因于miR-21缺陷通过miR-21靶向程序性细胞死亡4（PDCD 4）抑制骨吸收和破骨细胞功能，尽管存在RANKL。据我们所知，这是第一个在体内发现前骨细胞microRNA的证据。总之，这些发现阐明了miR-21在骨代谢中的功能，特别是揭示了miR-21失活在骨质疏松症中的骨保护潜力。
MicroRNAs emerge as critical post-transcriptional regulators in bone metabolism. We have previously reportedin vitrothat miR-21 promotes osteogenesis, while studies have also revealed miR-21 as a regulator of osteoclastogenesis and a promoter of osteoclast differentiationin vitro. However,in vivodata are still lacking in identifying skeletal function of miR-21, particularly its effects on osteoporosis. Here, using miR-21 knockout (miR-21−/−) mice, we investigated effects of miR-21 on bone development, bone remodeling and bone loss. Unexpectedly, miR-21−/−mice demonstrated normal skeletal phenotype in development and maintained osteoblastogenesisin vivo. Besides, miR-21−/−mice showed increased receptor activator of nuclear factor κB ligand (RANKL) and decreased osteoprotegerin (OPG) through miR-21 targeting Sprouty 1 (Spry1). Nevertheless, interestingly, miR-21 deficiency promoted trabecular bone mass accrual physiologically. Furthermore, in pathological states, the protection of bone mass was prominent in miR-21−/−mice. These skeletal effects were attributed to inhibition of bone resorption and osteoclast function by miR-21 deficiency through miR-21 targeting programmed cell death 4 (PDCD4), despite the existence of RANKL. As far as we know, this is the firstin vivoevidence of a pro-osteoclastic microRNA. Together, these findings clarified function of miR-21 in bone metabolism, particularly uncovering osteo-protective potential of miR-21 inactivation in osteoporosis.