SMURF2 regulates bone homeostasis by disrupting SMAD3 interaction with vitamin D receptor in osteoblasts.
SMURF2 regulates bone homeostasis by disrupting SMAD3 interaction with vitamin D receptor in osteoblasts.
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SMURF2 通过破坏 SMAD3 与成骨细胞中维生素 D 受体的相互作用来调节骨稳态。
DOI：
10.1038/ncomms14570
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发表时间：
2017-02-20
影响因子：
16.6
通讯作者：
Zou W
中科院分区：
文献类型：
--
作者：
Xu Z;Greenblatt MB;Yan G;Feng H;Sun J;Lotinun S;Brady N;Baron R;Glimcher LH;Zou W
成骨细胞和破骨细胞之间的协调是骨骼健康和体内平衡所必需的。在这里，我们发现SMURF 2缺陷的小鼠在体内具有严重的骨质疏松症。这种低骨量表型伴随着破骨细胞数量的显著增加，尽管Smurf2缺陷型破骨细胞的活性没有内在的改变。Smurf2缺陷型成骨细胞显示RANKL（中枢破骨细胞生成细胞因子）表达增加。从机制上讲，SMURF2通过改变SMAD3泛素化破坏SMAD3与维生素D受体之间的相互作用来调节RANKL表达。成骨细胞谱系中Smurf2的选择性缺失重现了种系Smurf2缺陷小鼠的表型，表明SMURF2调节成骨细胞依赖性破骨细胞活性，而不是直接影响破骨细胞。我们的研究结果表明，SMURF2作为成骨细胞和破骨细胞之间的关键通信的重要调节器。此外，Smurf2和Smurf1缺陷小鼠的骨量表型是相反的，表明SMURF 2与SMURF 1具有非重叠的功能，在某些方面，相反的功能。破骨细胞和成骨细胞介导的骨转换之间的平衡对于骨健康和稳态是必不可少的。在这里，作者表明，生殖系和成骨细胞特异性Smurf2缺陷小鼠都有骨质疏松症，这是由于成骨细胞RANKL产生增加和破骨细胞过度生成。
Coordination between osteoblasts and osteoclasts is required for bone health and homeostasis. Here we show that mice deficient in SMURF2 have severe osteoporosis in vivo. This low bone mass phenotype is accompanied by a pronounced increase in osteoclast numbers, although Smurf2-deficient osteoclasts have no intrinsic alterations in activity. Smurf2-deficient osteoblasts display increased expression of RANKL, the central osteoclastogenic cytokine. Mechanistically, SMURF2 regulates RANKL expression by disrupting the interaction between SMAD3 and vitamin D receptor by altering SMAD3 ubiquitination. Selective deletion of Smurf2 in the osteoblast lineage recapitulates the phenotype of germline Smurf2-deficient mice, indicating that SMURF2 regulates osteoblast-dependent osteoclast activity rather than directly affecting the osteoclast. Our results reveal SMURF2 as an important regulator of the critical communication between osteoblasts and osteoclasts. Furthermore, the bone mass phenotype in Smurf2- and Smurf1-deficient mice is opposite, indicating that SMURF2 has a non-overlapping and, in some respects, opposite function to SMURF1. The balance between osteoclast and osteoblast-mediated bone turnover is essential for bone health and homeostasis. Here the authors show that both germline and osteoblast-specific Smurf2-deficient mice have osteoporosis as a result of increased osteoblast RANKL production and excess osteoclastogenesis.