锌转运蛋白SLC39A13/ZIP13是结缔组织发育所必需的；它参与骨形态发生蛋白/转化生长因子-β信号通路。

The zinc transporter SLC39A13/ZIP13 is required for connective tissue development; its involvement in BMP/TGF-beta signaling pathways.

作者信息

Fukada Toshiyuki, Civic Natacha, Furuichi Tatsuya, Shimoda Shinji, Mishima Kenji, Higashiyama Hiroyuki, Idaira Yayoi, Asada Yoshinobu, Kitamura Hiroshi, Yamasaki Satoru, Hojyo Shintaro, Nakayama Manabu, Ohara Osamu, Koseki Haruhiko, Dos Santos Heloisa G, Bonafe Luisa, Ha-Vinh Russia, Zankl Andreas, Unger Sheila, Kraenzlin Marius E, Beckmann Jacques S, Saito Ichiro, Rivolta Carlo, Ikegawa Shiro, Superti-Furga Andrea, Hirano Toshio

机构信息

Laboratory for Cytokine Signaling, RIKEN Research Center for Allergy and Immunology, Tsurumi, Yokohama, Kanagawa, Japan.

出版信息

PLoS One. 2008;3(11):e3642. doi: 10.1371/journal.pone.0003642. Epub 2008 Nov 5.

BACKGROUND

Zinc (Zn) is an essential trace element and it is abundant in connective tissues, however biological roles of Zn and its transporters in those tissues and cells remain unknown.

METHODOLOGY/PRINCIPAL FINDINGS: Here we report that mice deficient in Zn transporter Slc39a13/Zip13 show changes in bone, teeth and connective tissue reminiscent of the clinical spectrum of human Ehlers-Danlos syndrome (EDS). The Slc39a13 knockout (Slc39a13-KO) mice show defects in the maturation of osteoblasts, chondrocytes, odontoblasts, and fibroblasts. In the corresponding tissues and cells, impairment in bone morphogenic protein (BMP) and TGF-beta signaling were observed. Homozygosity for a SLC39A13 loss of function mutation was detected in sibs affected by a unique variant of EDS that recapitulates the phenotype observed in Slc39a13-KO mice.

CONCLUSIONS/SIGNIFICANCE: Hence, our results reveal a crucial role of SLC39A13/ZIP13 in connective tissue development at least in part due to its involvement in the BMP/TGF-beta signaling pathways. The Slc39a13-KO mouse represents a novel animal model linking zinc metabolism, BMP/TGF-beta signaling and connective tissue dysfunction.

背景

锌（Zn）是一种必需的微量元素，在结缔组织中含量丰富，然而锌及其转运蛋白在这些组织和细胞中的生物学作用仍不清楚。

方法/主要发现：在此我们报告，锌转运蛋白Slc39a13/Zip13缺陷的小鼠在骨骼、牙齿和结缔组织方面出现的变化使人联想到人类埃勒斯-当洛综合征（EDS）的临床症状谱。Slc39a13基因敲除（Slc39a13-KO）小鼠在成骨细胞、软骨细胞、成牙本质细胞和成纤维细胞的成熟过程中表现出缺陷。在相应的组织和细胞中，观察到骨形态发生蛋白（BMP）和转化生长因子-β（TGF-β）信号传导受损。在受一种独特的EDS变异影响的同胞中检测到SLC39A13功能丧失突变的纯合性，该变异重现了在Slc39a13-KO小鼠中观察到的表型。

结论/意义：因此，我们的结果揭示了SLC39A13/ZIP13在结缔组织发育中的关键作用，至少部分原因是它参与了BMP/TGF-β信号通路。Slc39a13-KO小鼠代表了一种将锌代谢、BMP/TGF-β信号传导和结缔组织功能障碍联系起来的新型动物模型。