title: CXXC5 is a negative-feedback regulator of the Wnt/β-catenin pathway involved in osteoblast differentiation.
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.
authors: 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.
authors: H-Y
authors: HY
authors: Kim
authors: 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.
authors: J-Y
authors: JY
authors: Yoon
authors: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.
authors: J-H
authors: JH
authors: Yun
authors: Department of Oral Biology, Research Center for Orofacial Hard Tissue Regeneration, College of Dentistry, Yonsei University, Seoul, Korea.
authors: K-W
authors: KW
authors: Cho
authors: 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.
authors: S-H
authors: SH
authors: Lee
authors: Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
authors: Y-M
authors: YM
authors: Rhee
authors: Department of Oral Biology, Research Center for Orofacial Hard Tissue Regeneration, College of Dentistry, Yonsei University, Seoul, Korea.
authors: H-S
authors: HS
authors: Jung
authors: Korea Research Institute of Chemical Technology, Daejeon, Korea.
authors: H J
authors: HJ
authors: Lim
authors: Korea Research Institute of Chemical Technology, Daejeon, Korea.
authors: H
authors: H
authors: Lee
authors: Bioinformatics and Molecular Design Research Center, Yonsei University, Seoul, Korea.
authors: J
authors: J
authors: Choi
authors: Korea Research Institute of Chemical Technology, Daejeon, Korea.
authors: J-N
authors: JN
authors: Heo
authors: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.
authors: W
authors: W
authors: Lee
authors: 1] Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea [2] Bioinformatics and Molecular Design Research Center, Yonsei University, Seoul, Korea.
authors: K T
authors: KT
authors: No
authors: 1] Translational Research Center for Protein Function Control, Yonsei University, Seoul, Korea [2] Department of Molecular Biology, College of Natural Science, Pusan National University, Busan, Korea.
authors: D
authors: D
authors: Min
authors: 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.
authors: K-Y
authors: KY
authors: Choi
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D010006:Osteoblasts / Q000166:cytology* / Q000378:metabolism*; D054380:Receptors, CXCR5 / Q000235:genetics / Q000378:metabolism*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000502:physiology*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D054380:Receptors, CXCR5; D051153:Wnt Proteins; D051176:beta Catenin
references: Bone. 2000 Apr;26(4):375-80
references: 10719281
references: Mol Cell Biol. 2001 Jan;21(1):330-42
references: 11113207
references: Genome Res. 2003 Jun;13(6B):1430-42
references: 12819142
references: Biochem Biophys Res Commun. 2004 Sep 10;322(1):326-32
references: 15313210
references: Calcif Tissue Res. 1972;10(4):302-13
references: 4345096
references: J Bone Miner Res. 1987 Dec;2(6):595-610
references: 3455637
references: Avian Dis. 1992 Apr-Jun;36(2):447-9
references: 1627115
references: Science. 1998 Sep 4;281(5382):1509-12
references: 9727977
references: Proc Natl Acad Sci U S A. 1999 May 11;96(10):5522-7
references: 10318916
references: J Bone Miner Res. 1999 Jun;14(6):893-903
references: 10352097
references: J Mol Med (Berl). 2005 May;83(5):324-8
references: 15703950
references: J Biol Chem. 2005 May 20;280(20):19883-7
references: 15778503
references: J Biol Chem. 2007 Feb 9;282(6):3653-63
references: 17158875
references: N Engl J Med. 2007 Aug 30;357(9):905-16
references: 17761594
references: J Dent Res. 2007 Dec;86(12):1134-41
references: 18037646
references: Bone. 2008 Apr;42(4):606-15
references: 18280232
references: J Biol Chem. 2009 Feb 6;284(6):3672-81
references: 19001364
references: Expert Opin Ther Targets. 2009 Apr;13(4):485-96
references: 19335070
references: Blood. 2009 Apr 2;113(14):3172-81
references: 19182210
references: Rev Endocr Metab Disord. 2010 Dec;11(4):219-27
references: 21188536
references: Lancet. 2011 Apr 9;377(9773):1276-87
references: 21450337
references: Nat Rev Mol Cell Biol. 2012 Jan;13(1):27-38
references: 22189423
references: Cold Spring Harb Perspect Biol. 2012 Dec;4(12). pii: a007997. doi: 10.1101/cshperspect.a007997
references: 23209148
references: FASEB J. 2014 Feb;28(2):615-26
references: 24136587