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

Tommy Noh, Yankel Gabet, Jon Cogan, Yunfan Shi, Archana Tank, Tomoyo Sasaki, Braden Criswell, Alexis Dixon, Christopher Lee, Joseph Tam, Thomas Kohler, Eran Segev, Lisa Kockeritz, James Woodgett, Ralph Müller, Yang Chai, Elisheva Smith, Itai Bab, Baruch Frenkel*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

58 Scopus citations

Abstract

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 Gsk3β, 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.

Original languageAmerican English
Article numbere5438
JournalPLoS ONE
Volume4
Issue number5
DOIs
StatePublished - 4 May 2009

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