A novel Hoxd13 mutation causes synpolydactyly and promotes osteoclast differentiation by regulating pSmad5/p65/c-Fos/Rank axis.
A novel Hoxd13 mutation causes synpolydactyly and promotes osteoclast differentiation by regulating pSmad5/p65/c-Fos/Rank axis.
复制标题
DOI：
10.1038/s41419-023-05681-8
复制
发表时间：
2023-02-20
影响因子：
9
通讯作者：
Lin, Yanliang
中科院分区：
文献类型：
--
作者：
Zhang, Lishan;Fang, Ziqi;Cheng, Guangdong;He, Mengting;Lin, Yanliang
Hoxd13基因的突变与并指畸形有关，Hoxd13基因的聚丙氨酸延伸突变可导致小鼠的并多指畸形。本研究在一个中国人SPD家系中发现了一个新的Hoxd13错义突变(NM_000523：外显子2：C.G917T：p.R306L)。产生了携带相应Hoxd13突变的小鼠。结果表明，Hoxd13纯合子突变也可引起SPD，但杂合突变不影响肢体发育，这与SPD患者不同。随着世代的增加，携带Hoxd13纯合子突变的小鼠出现更严重的并指。Western blotting显示该突变不影响Hoxd13的蛋白表达，表明该突变不会导致单倍体功能不全。进一步分析表明，该纯合子Hoxd13突变促进了破骨细胞分化和骨丢失，并增强了破骨细胞相关基因Rank、c-Fos和p65的mRNA和蛋白表达。同时，这种纯合子Hoxd13突变提高了磷酸化Smad5(PSmad5)的水平。免疫共沉淀证实，该突变减弱了pSmad5和Hoxd13之间的相互作用，表明该突变释放了更多的pSmad5。抑制pSmad5使Rank、c-Fos和p65的表达减少，尽管在突变组。此外，pSmad5的抑制抑制了破骨细胞的分化。芯片检测证实p65和c-Fos能与Rank启动子结合。这些结果提示，这种新的Hoxd13突变可能通过调节Smad5/p65/c-Fos/Rank轴来促进破骨细胞分化，这可能为SPD的发生发展提供新的视角。
The mutations of HOXD13 gene have been involved in synpolydactyly (SPD), and the polyalanine extension mutation of Hoxd13 gene could lead to SPD in mice. In this study, a novel missense mutation of Hoxd13 (NM_000523: exon2: c.G917T: p.R306L) was identified in a Chinese family with SPD. The mice carrying the corresponding Hoxd13mutation were generated. The results showed that the homozygous mutation of Hoxd13 also caused SPD, but heterozygous mutation did not affect limbs development, which was different from that of SPD patients. With the increasing generation, the mice with homozygous Hoxd13 mutation presented more severe syndactyly. Western blotting showed that this mutation did not affect the protein expression of Hoxd13, suggesting that this mutation did not result in haploinsufficiency. Further analysis demonstrated that this homozygous Hoxd13mutation promoted osteoclast differentiation and bone loss, and enhanced the mRNA and protein expression of osteoclast-related genes Rank, c-Fos, and p65. Meanwhile, this homozygous Hoxd13 mutation elevated the level of phosphorylated Smad5 (pSmad5). Co-immunoprecipitation verified that this mutation attenuated the interaction between pSmad5 and HOXD13, suggesting that this mutation released more pSmad5. Inhibition of pSmad5 reduced the expression of Rank, c-Fos, and p65 despite in the mutation group. In addition, inhibition of pSmad5 repressed the osteoclast differentiation. ChIP assay confirmed that p65 and c-Fos could bind to the promoter of Rank. These results suggested that this novel Hoxd13 mutation promoted osteoclast differentiation by regulating Smad5/p65/c-Fos/Rank axis, which might provide a new insight into SPD development.
登录
查看更多内容
影响因子：
7
作者：
Ibrahim DM;Hansen P;Rödelsperger C;Stiege AC;Doelken SC;Horn D;Jäger M;Janetzki C;Krawitz P;Leschik G;Wagner F;Scheuer T;Schmidt-von Kegler M;Seemann P;Timmermann B;Robinson PN;Mundlos S;Hecht J
通讯作者：
Hecht J
HOXD13 同源域突变导致两个中国家族 1-c 型并指
影响因子：
3.7
作者：
Dai L;Liu D;Song M;Xu X;Xiong G;Yang K;Zhang K;Meng H;Guo H;Bai Y
通讯作者：
Bai Y
影响因子：
64.5
作者：
Basu, Shaon;Mackowiak, Sebastian D.;Hnisz, Denes
通讯作者：
Hnisz, Denes
影响因子：
3.5
作者：
Fantini, Sebastian;Vaccari, Giulia;Zappavigna, Vincenzo
通讯作者：
Zappavigna, Vincenzo
DOI：
10.1196/annals.1365.035
发表时间：
2006-01-01
期刊：
WOMEN'S HEALTH AND DISEASE: GYNECOLOGIC, ENDOCRINE, AND REPRODUCTIVE ISSUES
影响因子：
--
作者：
Hadjidakis, Dimitrios J.;Androulakis, Ioannis I.
通讯作者：
Androulakis, Ioannis I.