Targeted deletion of the sclerostin gene in mice results in increased bone formation and bone strength.
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.
Li
Xiaodong
X
Department of Metabolic Disorders, Amgen, Thousand Oaks, California 91320-1799, USA.
Ominsky
Michael S
MS
Niu
Qing-Tian
QT
Sun
Ning
N
Daugherty
Betsy
B
D'Agostin
Diane
D
Kurahara
Carole
C
Gao
Yongming
Y
Cao
Jin
J
Gong
Jianhua
J
Asuncion
Frank
F
Barrero
Mauricio
M
Warmington
Kelly
K
Dwyer
Denise
D
Stolina
Marina
M
Morony
Sean
S
Sarosi
Ildiko
I
Kostenuik
Paul J
PJ
Lacey
David L
DL
Simonet
W Scott
WS
Ke
Hua Zhu
HZ
Paszty
Chris
C
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
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