naa a22 4500 528785001 20180924065518.0 cr unu---uuuuu 180924e20090504xx s 000 0 eng 10.3929/ethz-b-000015353 doi 10.1371/journal.pone.0005438 doi (ETHRESEARCH)oai:www.research-collection.ethz.ch:20.500.11850/15353 Lef1 Haploinsufficient Mice Display a Low Turnover and Low Bone Mass Phenotype in a Gender- and Age-Specific Manner [Elektronische Daten] [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; id_orcid 0000-0002-5811-7725 Müller, Yang Chai, Elisheva Smith, Itai Bab, Baruch Frenkel] PLoS ONE Open access ethresearch 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. Creative Commons Attribution 3.0 Unported http://creativecommons.org/licenses/by/3.0 ethresearch Noh Tommy joint author Gabet Yankel joint author Cogan Jon joint author Shi Yunfan joint author Tank Archana joint author Sasaki Tomoyo joint author Criswell Braden joint author Dixon Alexis joint author Lee Christopher joint author Tam Joseph joint author Kohler Thomas joint author Segev Eran joint author Kockeritz Lisa joint author Woodgett James joint author Müller Ralph; id_orcid 0000-0002-5811-7725 joint author Chai Yang joint author Smith Elisheva joint author Bab Itai joint author Frenkel Baruch joint author PLoS ONE Lawrence, KS, USA : Public Library of Science 4 (5), p. e5438 1932-6203 http://hdl.handle.net/20.500.11850/15353 text/html WWW-Backlink auf das Repository (Open access) 1 Journal Article ethresearch ETHRESEARCH 856 40 http://hdl.handle.net/20.500.11850/15353 text/html WWW-Backlink auf das Repository (Open access) ETHRESEARCH 700 1- Noh Tommy joint author ETHRESEARCH 700 1- Gabet Yankel joint author ETHRESEARCH 700 1- Cogan Jon joint author ETHRESEARCH 700 1- Shi Yunfan joint author ETHRESEARCH 700 1- Tank Archana joint author ETHRESEARCH 700 1- Sasaki Tomoyo joint author ETHRESEARCH 700 1- Criswell Braden joint author ETHRESEARCH 700 1- Dixon Alexis joint author ETHRESEARCH 700 1- Lee Christopher joint author ETHRESEARCH 700 1- Tam Joseph joint author ETHRESEARCH 700 1- Kohler Thomas joint author ETHRESEARCH 700 1- Segev Eran joint author ETHRESEARCH 700 1- Kockeritz Lisa joint author ETHRESEARCH 700 1- Woodgett James joint author ETHRESEARCH 700 1- Müller Ralph; id_orcid 0000-0002-5811-7725 joint author ETHRESEARCH 700 1- Chai Yang joint author ETHRESEARCH 700 1- Smith Elisheva joint author ETHRESEARCH 700 1- Bab Itai joint author ETHRESEARCH 700 1- Frenkel Baruch joint author ETHRESEARCH 773 0- PLoS ONE Lawrence, KS, USA : Public Library of Science 4 (5), p. e5438 1932-6203 BK010053 XK010053 XK010000 ETHRESEARCH ETHRESEARCH ETHRESEARCH Journal Article Open access