title: Osteoclast-secreted CTHRC1 in the coupling of bone resorption to formation.
abstract: Bone remodeling is characterized by the sequential, local tethering of osteoclasts and osteoblasts and is key to the maintenance of bone integrity. While bone matrix-mobilized growth factors, such as TGF-β, are proposed to regulate remodeling, no in vivo evidence exists that an osteoclast-produced molecule serves as a coupling factor for bone resorption to formation. We found that CTHRC1, a protein secreted by mature bone-resorbing osteoclasts, targets stromal cells to stimulate osteogenesis. Cthrc1 expression was robustly induced when mature osteoclasts were placed on dentin or hydroxyapatite, and also by increasing extracellular calcium. Cthrc1 expression in bone increased in a high-turnover state (such as that induced by RANKL injections in vivo), but decreased in conditions associated with suppressed bone turnover (such as with aging and after alendronate treatment). Targeted deletion of Cthrc1 in mice eliminated Cthrc1 expression in bone, whereas its deficiency in osteoblasts did not exert any significant effect. Osteoclast-specific deletion of Cthrc1 resulted in osteopenia due to reduced bone formation and impaired the coupling process after resorption induced by RANKL injections, impairing bone mass recovery. These data demonstrate that CTHRC1 is an osteoclast-secreted coupling factor that regulates bone remodeling.
authors.affiliation: Department of Bone and Joint Disease, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan. sunao@ncgg.go.jp
authors.forename: Sunao
authors.initials: S
authors.lastname: Takeshita
authors.forename: Toshio
authors.initials: T
authors.lastname: Fumoto
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Matsuoka
authors.forename: Kyoung-ae
authors.initials: KA
authors.lastname: Park
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Aburatani
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Kato
authors.forename: Masako
authors.initials: M
authors.lastname: Ito
authors.forename: Kyoji
authors.initials: K
authors.lastname: Ikeda
mesh_terms: D041721:3T3-L1 Cells; D000818:Animals; D001862:Bone Resorption / Q000378:metabolism*; D002118:Calcium / Q000494:pharmacology; D002454:Cell Differentiation; D002478:Cells, Cultured; D017886:Durapatite / Q000494:pharmacology; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010010:Osteoclasts / Q000378:metabolism*; D010012:Osteogenesis
chemical_list: C530500:Cthrc1 protein, mouse; D016326:Extracellular Matrix Proteins; D017886:Durapatite; D002118:Calcium
references.citation: Trends Mol Med. 2005 Feb;11(2):76-81
references.pmid: 15694870
references.citation: Surg Forum. 1964;15:437-8
references.pmid: 14189452
references.citation: J Bone Miner Res. 2009 Jul;24(7):1194-205
references.pmid: 19257825
references.citation: Nat Med. 2006 Dec;12(12):1403-9
references.pmid: 17128270
references.citation: J Bone Miner Res. 2000 Aug;15(8):1477-88
references.pmid: 10934646
references.citation: Development. 2006 Aug;133(16):3231-44
references.pmid: 16854976
references.citation: N Engl J Med. 2003 Sep 25;349(13):1207-15
references.pmid: 14500804
references.citation: Endocr Rev. 2005 May;26(3):439-51
references.pmid: 15897298
references.citation: EMBO J. 2006 Dec 13;25(24):5840-51
references.pmid: 17124500
references.citation: Dev Cell. 2002 Apr;2(4):389-406
references.pmid: 11970890
references.citation: Nat Med. 2002 Sep;8(9):943-9
references.pmid: 12161749
references.citation: Circ Res. 2005 Feb 4;96(2):261-8
references.pmid: 15618538
references.citation: Nature. 1965 May 1;206(983):489-90
references.pmid: 5319106
references.citation: Cell Stem Cell. 2010 Nov 5;7(5):571-80
references.pmid: 21040899
references.citation: Bone. 2009 Feb;44(2):199-207
references.pmid: 18845279
references.citation: Nat Med. 2009 Mar;15(3):259-66
references.pmid: 19252502
references.citation: Cell Metab. 2006 Aug;4(2):111-21
references.pmid: 16890539
references.citation: J Bone Miner Res. 2013 Jan;28(1):2-17
references.pmid: 23197339
references.citation: Biochem Biophys Res Commun. 2004 Aug 20;321(2):275-9
references.pmid: 15358172
references.citation: Nature. 2009 Mar 26;458(7237):524-8
references.pmid: 19204730
references.citation: J Clin Invest. 2013 Feb;123(2):666-81
references.pmid: 23321671
references.citation: Endocr Rev. 2011 Feb;32(1):31-63
references.pmid: 20851921
references.citation: Nat Med. 2009 Jul;15(7):757-65
references.pmid: 19584867
references.citation: Nat Med. 2007 Jul;13(7):791-801
references.pmid: 17618270
references.citation: Dev Cell. 2008 Jul;15(1):23-36
references.pmid: 18606138
references.citation: J Bone Miner Res. 2005 Oct;20(10):1828-36
references.pmid: 16160740
references.citation: Cell. 2007 Sep 7;130(5):811-23
references.pmid: 17803905
references.citation: Trends Cardiovasc Med. 2007 Aug;17(6):202-5
references.pmid: 17662915
references.citation: Science. 1999 Dec 3;286(5446):1946-9
references.pmid: 10583956
references.citation: Proc Natl Acad Sci U S A. 1981 May;78(5):3204-8
references.pmid: 6942425
references.citation: PLoS One. 2008 Sep 09;3(9):e3174
references.pmid: 18779865
references.citation: Proc Natl Acad Sci U S A. 2008 Dec 30;105(52):20764-9
references.pmid: 19075223
references.citation: J Bone Miner Res. 2010 Jul;25(7):1468-86
references.pmid: 20533309
references.citation: Am J Pathol. 2005 Feb;166(2):467-76
references.pmid: 15681830
references.citation: J Bone Miner Res. 2012 Mar;27(3):506-8
references.pmid: 22354850
references.citation: Cell Metab. 2007 Jun;5(6):464-75
references.pmid: 17550781
references.citation: Gene Expr Patterns. 2006 Oct;6(8):935-40
references.pmid: 16678498