2. Academic Validation
  3. CXXC5 mediates growth plate senescence and is a target for enhancement of longitudinal bone growth

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

  • Life Sci Alliance. 2019 Apr 10;2(2):e201800254. doi: 10.26508/lsa.201800254.
Sehee Choi 1 2,  Hyun-Yi Kim 1 2,  Pu-Hyeon Cha 1 2,  Seol Hwa Seo 1 2,  Chulho Lee 1 2,  Yejoo Choi 1 2,  Wookjin Shin 1 2,  Yunseok Heo 1 3,  Gyoonhee Han 1 2,  Weontae Lee 1 3,  Kang-Yell Choi 4 2 5
Affiliations

Affiliations

  • 1 Translational Research Center for Protein Function Control, Yonsei University, Seoul, Korea.
  • 2 Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.
  • 3 Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.
  • 4 Translational Research Center for Protein Function Control, Yonsei University, Seoul, Korea [email protected].
  • 5 CK Biotechnology Inc, Seoul, Korea.
PMID: 30971423 DOI: 10.26508/lsa.201800254
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 -/- 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.

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