title: Cthrc1 is a positive regulator of osteoblastic bone formation.
abstract: BACKGROUND
  Bone mass is maintained by continuous remodeling through repeated cycles of bone resorption by osteoclasts and bone formation by osteoblasts. This remodeling process is regulated by many systemic and local factors.
  
  
  RESULTS
  We identified collagen triple helix repeat containing-1 (Cthrc1) as a downstream target of bone morphogenetic protein-2 (BMP2) in osteochondroprogenitor-like cells by PCR-based suppression subtractive hybridization followed by differential hybridization, and found that Cthrc1 was expressed in bone tissues in vivo. To investigate the role of Cthrc1 in bone, we generated Cthrc1-null mice and transgenic mice which overexpress Cthrc1 in osteoblasts (Cthrc1 transgenic mice). Microcomputed tomography (micro-CT) and bone histomorphometry analyses showed that Cthrc1-null mice displayed low bone mass as a result of decreased osteoblastic bone formation, whereas Cthrc1 transgenic mice displayed high bone mass by increase in osteoblastic bone formation. Osteoblast number was decreased in Cthrc1-null mice, and increased in Cthrc1 transgenic mice, respectively, while osteoclast number had no change in both mutant mice. In vitro, colony-forming unit (CFU) assays in bone marrow cells harvested from Cthrc1-null mice or Cthrc1 transgenic mice revealed that Cthrc1 stimulated differentiation and mineralization of osteoprogenitor cells. Expression levels of osteoblast specific genes, ALP, Col1a1, and Osteocalcin, in primary osteoblasts were decreased in Cthrc1-null mice and increased in Cthrc1 transgenic mice, respectively. Furthermore, BrdU incorporation assays showed that Cthrc1 accelerated osteoblast proliferation in vitro and in vivo. In addition, overexpression of Cthrc1 in the transgenic mice attenuated ovariectomy-induced bone loss.
  
  
  CONCLUSIONS
  Our results indicate that Cthrc1 increases bone mass as a positive regulator of osteoblastic bone formation and offers an anabolic approach for the treatment of osteoporosis.
authors.affiliation: Department of Orthopaedics, Kyoto University, Kyoto, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kimura
authors.forename: Kin Ming
authors.initials: KM
authors.lastname: Kwan
authors.forename: Zhaoping
authors.initials: Z
authors.lastname: Zhang
authors.forename: Jian Min
authors.initials: JM
authors.lastname: Deng
authors.forename: Bryant G
authors.initials: BG
authors.lastname: Darnay
authors.forename: Richard R
authors.initials: RR
authors.lastname: Behringer
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakamura
authors.forename: Benoit
authors.initials: B
authors.lastname: de Crombrugghe
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Akiyama
mesh_terms: D000818:Animals; D016723:Bone Remodeling; D001842:Bone and Bones / Q000378:metabolism; D049109:Cell Proliferation; D016326:Extracellular Matrix Proteins / Q000378:metabolism / Q000502:physiology*; D005260:Female; D005786:Gene Expression Regulation; D016678:Genome; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D010006:Osteoblasts / Q000378:metabolism*; D010012:Osteogenesis; D010024:Osteoporosis / Q000175:diagnosis / Q000235:genetics
chemical_list: C502426:CTHRC1 protein, human; D016326:Extracellular Matrix Proteins
references.citation: Bone Miner. 1991 Dec;15(3):175-91
references.pmid: 1773131
references.citation: Annu Rev Cell Dev Biol. 2000;16:191-220
references.pmid: 11031235
references.citation: Nature. 2003 May 15;423(6937):349-55
references.pmid: 12748654
references.citation: J Bone Miner Res. 2000 Apr;15(4):663-73
references.pmid: 10780858
references.citation: Virchows Arch A Pathol Anat Histopathol. 1991;418(1):1-7
references.pmid: 1899163
references.citation: Nature. 2003 May 15;423(6937):332-6
references.pmid: 12748651
references.citation: J Bone Miner Res. 1987 Dec;2(6):595-610
references.pmid: 3455637
references.citation: Dev Cell. 2002 Apr;2(4):389-406
references.pmid: 11970890
references.citation: J Clin Invest. 2003 Sep;112(6):924-34
references.pmid: 12975477
references.citation: Circ Res. 2005 Feb 4;96(2):261-8
references.pmid: 15618538
references.citation: Curr Top Dev Biol. 2007;78:127-71
references.pmid: 17338916
references.citation: Calcif Tissue Int. 1988 Sep;43(3):179-83
references.pmid: 3141020
references.citation: J Bone Miner Res. 2006 Nov;21(11):1713-21
references.pmid: 17002585
references.citation: Ann N Y Acad Sci. 2006 Apr;1068:41-53
references.pmid: 16831904
references.citation: Science. 1988 Dec 16;242(4885):1528-34
references.pmid: 3201241
references.citation: Endocrinology. 2003 May;144(5):1972-8
references.pmid: 12697704
references.citation: Science. 2000 Sep 1;289(5484):1508-14
references.pmid: 10968781
references.citation: J Bone Miner Res. 1987 Apr;2(2):115-22
references.pmid: 3455160
references.citation: N Engl J Med. 2007 Aug 30;357(9):905-16
references.pmid: 17761594
references.citation: Clin Cancer Res. 2006 Jun 15;12(12):3716-22
references.pmid: 16778098
references.citation: Circ Res. 2007 Mar 30;100(6):826-33
references.pmid: 17322174
references.citation: J Cell Biol. 2002 Jun 10;157(6):1049-60
references.pmid: 12058020
references.citation: Cell. 2007 Sep 7;130(5):811-23
references.pmid: 17803905
references.citation: J Biol Chem. 2004 Jun 25;279(26):27560-6
references.pmid: 15090551
references.citation: Proc Natl Acad Sci U S A. 1997 Dec 23;94(26):14602-7
references.pmid: 9405659
references.citation: Cell. 2002 Jan 11;108(1):17-29
references.pmid: 11792318
references.citation: Endocrinology. 1995 Jun;136(6):2671-7
references.pmid: 7750491
references.citation: Biochem Biophys Res Commun. 2007 May 18;356(4):935-41
references.pmid: 17395156
references.citation: Bone. 1995 Jan;16(1):157-61
references.pmid: 7742075
references.citation: Cell. 2000 Dec 22;103(7):1085-97
references.pmid: 11163184
references.citation: J Cell Biol. 1995 Jun;129(5):1421-32
references.pmid: 7775585
references.citation: Gene Expr Patterns. 2006 Oct;6(8):935-40
references.pmid: 16678498