RT Journal Article
SR Electronic
T1 CXXC5 mediates growth plate senescence and is a target for enhancement of longitudinal bone growth
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e201800254
DO 10.26508/lsa.201800254
VO 2
IS 2
A1 Choi, Sehee
A1 Kim, Hyun-Yi
A1 Cha, Pu-Hyeon
A1 Seo, Seol Hwa
A1 Lee, Chulho
A1 Choi, Yejoo
A1 Shin, Wookjin
A1 Heo, Yunseok
A1 Han, Gyoonhee
A1 Lee, Weontae
A1 Choi, Kang-Yell
YR 2019
UL http://www.life-science-alliance.org/content/2/2/e201800254.abstract
AB 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.