CXXC5 mediates growth plate senescence and is a target for enhancement of longitudinal bone growth

被引：20

作者：

Choi, Sehee ^{[1
,2
]}

Kim, Hyun-Yi ^{[1
,2
]}

Cha, Pu-Hyeon ^{[1
,2
]}

Seo, Seol Hwa ^{[1
,2
]}

Lee, Chulho ^{[1
,2
]}

Choi, Yejoo ^{[1
,2
]}

Shin, Wookjin ^{[1
,2
]}

Heo, Yunseok ^{[1
,3
]}

Han, Gyoonhee ^{[1
,2
]}

Lee, Weontae ^{[1
,3
]}

Choi, Kang-Yell ^{[1
,2
,4
]}

机构：

[1] Yonsei Univ, Translat Res Ctr Prot Funct Control, Seoul, South Korea

[2] Yonsei Univ, Dept Biotechnol, Coll Life Sci & Biotechnol, Seoul, South Korea

[3] Yonsei Univ, Dept Biochem, Coll Life Sci & Biotechnol, Seoul, South Korea

[4] CK Biotechnol Inc, Seoul, South Korea

来源：

LIFE SCIENCE ALLIANCE | 2019年 / 2卷 / 02期

基金：

新加坡国家研究基金会;

关键词：

CARTILAGE; DIFFERENTIATION; INHIBITION; ESTROGENS; PATHWAY;

D O I：

10.26508/lsa.201800254

中图分类号：

Q [生物科学];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Longitudinal bone growth ceases with growth plate senescence during puberty. However, the molecular mechanisms of this phenomenon are largely unexplored. Here, we examined Wnt-responsive genes before and after growth plate senescence and found that CXXC finger protein 5 (CXXC5), a negative regulator of the Wnt/beta-catenin pathway, was gradually elevated with reduction of Wnt/beta-catenin signaling during senescent changes of rodent growth plate. Cxxc5(-/-) mice demonstrated delayed growth plate senescence and tibial elongation. As CXXC5 functions by interacting with dishevelled (DVL), we sought to identify small molecules capable of disrupting this interaction. In vitro screening assay monitoring CXXC5-DVL interaction revealed that several indirubin analogs were effective antagonists of this interaction. A functionally improved indirubin derivative, KY19382, elongated tibial length through delayed senescence and further activation of the growth plate in adolescent mice. Collectively, our findings reveal an important role for CXXC5 as a suppressor of longitudinal bone growth involving growth plate activity.

引用

页数：12

共 33 条

[1] CXXC5 Is a Novel BMP4-regulated Modulator of Wnt Signaling in Neural Stem Cells [J].