Abstract
The positive roles of the Wnt/β-catenin pathway in osteoblast differentiation and bone mineral density (BMD) maintenance have been clearly demonstrated in both animal experiments and clinical investigations. CXXC finger protein 5 (CXXC5), a recently identified negative regulator of the Wnt/β-catenin pathway, showed altered cellular localization and function, which were dependent on the cell type in previous studies. However, the in vivo function of CXXC5 has not been clearly investigated yet. Here, we characterized CXXC5 as a negative regulator of osteoblast differentiation and bone formation. Deficiency of CXXC5 resulted in elevated BMD in mice without any severe gross developmental abnormalities. CXXC5 exerted a negative-feedback effect on the Wnt/β-catenin pathway via Wnt-dependent binding to Dishevelled (Dvl) during osteoblast differentiation. Suppression of the Dvl–CXXC5 interaction using a competitor peptide resulted in the activation of the Wnt/β-catenin pathway and osteoblast differentiation, and accelerated thickness growth of ex vivo-cultured calvariae. Overall, CXXC5 is a negative-feedback regulator induced by Wnt/β-catenin signaling that inhibits osteoblast differentiation and bone formation via interaction with Dvl.
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Abbreviations
- α-MEM:
-
α-minimal essential medium
- ALP:
-
alkaline phosphatase
- BMD:
-
bone mineral density
- BSP:
-
bone sialoprotein
- CT:
-
computed tomography
- DAB:
-
3,3′-diaminobenzidine
- DBM:
-
Dvl-binding motif
- DMP-1:
-
dentin matrix acidic phosphoprotein-1
- Dvl:
-
Dishevelled
- Fgf18:
-
fibroblast growth factor 18
- H&E:
-
hematoxylin and eosin
- PTD:
-
protein transduction domain
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Acknowledgements
We thank Sean Bong Lee and Ho Jin Lee for their helpful discussion and comments on the manuscript. This work was funded by the Ministry of Future Creation and Science (MFCS) of Korea; Translational Research Center for Protein Function Control (2009-0083522), Mid-career Researcher Program (2012-010285) and Stem Cell Research Project (2010-0020235). This work was also supported by the Ministry of Knowledge Economy (through the Korea Research Institute of Chemical Technology (SI-0905, SI-1005, SI-1105, SI-1205 and SI-1304)). H-YK, J-YY, S-HL and K-WC were supported by a BK21 studentship from the NRF and the MFCS.
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Kim, HY., Yoon, JY., Yun, JH. et al. CXXC5 is a negative-feedback regulator of the Wnt/β-catenin pathway involved in osteoblast differentiation. Cell Death Differ 22, 912–920 (2015). https://doi.org/10.1038/cdd.2014.238
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DOI: https://doi.org/10.1038/cdd.2014.238
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