Lef1 haploinsufficient mice display a low turnover and low bone mass phenotype in a gender- and age-specific manner.
We investigated the role of Lef1, one of the four transcription factors that transmit Wnt signaling to the genome, in the regulation of bone mass. Microcomputed tomographic analysis of 13- and 17-week-old mice revealed significantly reduced trabecular bone mass in Lef1(+/-) females compared to littermate wild-type females. This was attributable to decreased osteoblast activity and bone formation as indicated by histomorphometric analysis of bone remodeling. In contrast to females, bone mass was unaffected by Lef1 haploinsufficiency in males. Similarly, females were substantially more responsive than males to haploinsufficiency in Gsk3beta, a negative regulator of the Wnt pathway, displaying in this case a high bone mass phenotype. Lef1 haploinsufficiency also led to low bone mass in males lacking functional androgen receptor (AR) (tfm mutants). The protective skeletal effect of AR against Wnt-related low bone mass is not necessarily a result of direct interaction between the AR and Wnt signaling pathways, because Lef1(+/-) female mice had normal bone mass at the age of 34 weeks. Thus, our results indicate an age- and gender-dependent role for Lef1 in regulating bone formation and bone mass in vivo. The resistance to Lef1 haploinsufficiency in males with active AR and in old females could be due to the reduced bone turnover in these mice.
Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
Tommy
T
Noh
Yankel
Y
Gabet
Jon
J
Cogan
Yunfan
Y
Shi
Archana
A
Tank
Tomoyo
T
Sasaki
Braden
B
Criswell
Alexis
A
Dixon
Christopher
C
Lee
Joseph
J
Tam
Thomas
T
Kohler
Eran
E
Segev
Lisa
L
Kockeritz
James
J
Woodgett
Ralph
R
Müller
Yang
Y
Chai
Elisheva
E
Smith
Itai
I
Bab
Baruch
B
Frenkel
D000367:Age Factors; D000818:Animals; D001483:Base Sequence; D015519:Bone Density / Q000235:genetics / Q000502:physiology*; D016723:Bone Remodeling / Q000235:genetics / Q000502:physiology*; D001842:Bone and Bones / Q000000981:diagnostic imaging; D017931:DNA Primers / Q000235:genetics; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D000071679:Glycogen Synthase Kinase 3 beta; D006579:Heterozygote; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011944:Receptors, Androgen / Q000172:deficiency / Q000235:genetics; D012737:Sex Factors; D015398:Signal Transduction; D014057:Tomography, X-Ray Computed; D051153:Wnt Proteins / Q000502:physiology
D017931:DNA Primers; C497574:Lef1 protein, mouse; D051821:Lymphoid Enhancer-Binding Factor 1; D012333:RNA, Messenger; D011944:Receptors, Androgen; D051153:Wnt Proteins; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3