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

Sehee Choi, Hyun Yi Kim, Pu Hyeon Cha, Seol Hwa Seo, Chulho Lee, Yejoo Choi, Wookjin Shin, Yunseok Heo, Gyoonhee Han, Weontae Lee, Kang Yell Choi

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

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/β-catenin pathway, was gradually elevated with reduction of Wnt/β-catenin signaling during senescent changes of rodent growth plate. Cxxc5 2 / 2 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.

Original languageEnglish
Article numbere201800254
JournalLife Science Alliance
Volume2
Issue number2
DOIs
Publication statusPublished - 2019

Bibliographical note

Funding Information:
We thank W-U Kim and E-H Jho for providing cells and reagents. This work was supported by the National Research Foundation of Korea grant funded by the Korean Government (MSIP) (grants 2015R1A2A1A05001873, 2016R1A5A1004694, 2019R1A2C3002751). S Choi, H-Y Kim, P-H Cha, SH Seo, and W Shin were supported by a BK21 PLUS program.

All Science Journal Classification (ASJC) codes

  • Ecology
  • Biochemistry, Genetics and Molecular Biology (miscellaneous)
  • Plant Science
  • Health, Toxicology and Mutagenesis

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