title: Targeted deletion of the sclerostin gene in mice results in increased bone formation and bone strength.
abstract: BACKGROUND
  Sclerosteosis is a rare high bone mass genetic disorder in humans caused by inactivating mutations in SOST, the gene encoding sclerostin. Based on these data, sclerostin has emerged as a key negative regulator of bone mass. We generated SOST knockout (KO) mice to gain a more detailed understanding of the effects of sclerostin deficiency on bone.
  
  
  METHODS
  Gene targeting was used to inactivate SOST and generate a line of SOST KO mice. Radiography, densitometry, microCT, histomorphometry, and mechanical testing were used to characterize the impact of sclerostin deficiency on bone in male and female mice. Comparisons were made between same sex KO and wildtype (WT) mice.
  
  
  RESULTS
  The results for male and female SOST KO mice were similar, with differences only in the magnitude of some effects. SOST KO mice had increased radiodensity throughout the skeleton, with general skeletal morphology being normal in appearance. DXA analysis of lumbar vertebrae and whole leg showed that there was a significant increase in BMD (>50%) at both sites. microCT analysis of femur showed that bone volume was significantly increased in both the trabecular and cortical compartments. Histomorphometry of trabecular bone revealed a significant increase in osteoblast surface and no significant change in osteoclast surface in SOST KO mice. The bone formation rate in SOST KO mice was significantly increased for trabecular bone (>9-fold) at the distal femur, as well as for the endocortical and periosteal surfaces of the femur midshaft. Mechanical testing of lumbar vertebrae and femur showed that bone strength was significantly increased at both sites in SOST KO mice.
  
  
  CONCLUSIONS
  SOST KO mice have a high bone mass phenotype characterized by marked increases in BMD, bone volume, bone formation, and bone strength. These results show that sclerostin is a key negative regulator of a powerful, evolutionarily conserved bone formation pathway that acts on both trabecular and cortical bone.
authors.affiliation: Department of Metabolic Disorders, Amgen, Thousand Oaks, California 91320-1799, USA.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Li
authors.forename: Michael S
authors.initials: MS
authors.lastname: Ominsky
authors.forename: Qing-Tian
authors.initials: QT
authors.lastname: Niu
authors.forename: Ning
authors.initials: N
authors.lastname: Sun
authors.forename: Betsy
authors.initials: B
authors.lastname: Daugherty
authors.forename: Diane
authors.initials: D
authors.lastname: D'Agostin
authors.forename: Carole
authors.initials: C
authors.lastname: Kurahara
authors.forename: Yongming
authors.initials: Y
authors.lastname: Gao
authors.forename: Jin
authors.initials: J
authors.lastname: Cao
authors.forename: Jianhua
authors.initials: J
authors.lastname: Gong
authors.forename: Frank
authors.initials: F
authors.lastname: Asuncion
authors.forename: Mauricio
authors.initials: M
authors.lastname: Barrero
authors.forename: Kelly
authors.initials: K
authors.lastname: Warmington
authors.forename: Denise
authors.initials: D
authors.lastname: Dwyer
authors.forename: Marina
authors.initials: M
authors.lastname: Stolina
authors.forename: Sean
authors.initials: S
authors.lastname: Morony
authors.forename: Ildiko
authors.initials: I
authors.lastname: Sarosi
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Kostenuik
authors.forename: David L
authors.initials: DL
authors.lastname: Lacey
authors.forename: W Scott
authors.initials: WS
authors.lastname: Simonet
authors.forename: Hua Zhu
authors.initials: HZ
authors.lastname: Ke
authors.forename: Chris
authors.initials: C
authors.lastname: Paszty
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D015415:Biomarkers / Q000097:blood; D015519:Bone Density; D019485:Bone Morphogenetic Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000378:metabolism*; D002118:Calcium / Q000097:blood; D005260:Female; D017353:Gene Deletion; D005819:Genetic Markers / Q000235:genetics; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010012:Osteogenesis; D010641:Phenotype; D010710:Phosphates / Q000097:blood; D013314:Stress, Mechanical; D014057:Tomography, X-Ray Computed
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015415:Biomarkers; D019485:Bone Morphogenetic Proteins; D005819:Genetic Markers; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D010710:Phosphates; C486030:Sost protein, mouse; D002118:Calcium