Lef1 haploinsufficient mice display a low turnover and low bone mass phenotype in a gender- and age-specific manner

• Published in: PloS one Vol. 4; no. 5; p. e5438
• Main Authors: Noh, Tommy, Gabet, Yankel, Cogan, Jon, Shi, Yunfan, Tank, Archana, Sasaki, Tomoyo, Criswell, Braden, Dixon, Alexis, Lee, Christopher, Tam, Joseph, Kohler, Thomas, Segev, Eran, Kockeritz, Lisa, Woodgett, James, Müller, Ralph, Chai, Yang, Smith, Elisheva, Bab, Itai, Frenkel, Baruch
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 04.05.2009; Public Library of Science (PLoS)
• Subjects: Age; Age Factors; Androgen receptors; Animals; Base Sequence; Biochemistry; Biocompatibility; Biomechanics; Biomedical materials; Bone (trabecular); Bone and Bones - diagnostic imaging; Bone Density - genetics; Bone Density - physiology; Bone growth; Bone mass; Bone remodeling; Bone Remodeling - genetics; Bone Remodeling - physiology; Bone turnover; Cancellous bone; Computed tomography; Dentistry; Diabetes and Endocrinology/Bone and Mineral Metabolism; DNA Primers - genetics; Female; Females; Gene expression; Genomes; Genotype & phenotype; Glycogen Synthase Kinase 3 - deficiency; Glycogen Synthase Kinase 3 - genetics; Glycogen Synthase Kinase 3 - physiology; Glycogen Synthase Kinase 3 beta; Haploinsufficiency; Heterozygote; Kinases; Laboratories; Light emitting diodes; Lymphoid Enhancer-Binding Factor 1 - deficiency; Lymphoid Enhancer-Binding Factor 1 - genetics; Lymphoid Enhancer-Binding Factor 1 - physiology; Male; Males; Mammals; Medicine; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Mutant Strains; Molecular biology; Mutants; Nervous system; Osteogenesis; Osteoporosis; Phenotype; Physiology/Endocrinology; Proteins; Receptors, Androgen - deficiency; Receptors, Androgen - genetics; Rheumatology/Bone and Mineral Metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Sex Factors; Signal Transduction; Tomography, X-Ray Computed; Transcription factors; Wnt protein; Wnt Proteins - physiology; Los Angeles California; California; Israel; Jerusalem Israel; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0005438

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.