Lef1 Haploinsufficient Mice Display a Low Turnover and Low Bone Mass Phenotype in a Gender- and Age-Specific Manner

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.

Protein Kinase G and Focal Adhesion Kinase Converge on Src/Akt/β-Catenin Signaling Module in Osteoblast Mechanotransduction

“…Thus, increased PGE 2 synthesis may contribute to activation of PI3K/Akt/GSK-3/␤-catenin signaling in shearstressed osteoblasts and osteocytes, especially at later time points. The skeletal phenotypes of mice with genetic alterations in the PI3K/Akt/GSK-3 pathway confirm the importance of this pathway for regulating bone formation and stimulating osteoblast differentiation (58,60,61).…”

Osteocyte Wnt/β-Catenin Signaling Is Required for Normal Bone Homeostasis

“…Gender-specific enhanced sensitivity of female mice toward modulation of Wnt/␤-catenin signaling was also reported for other loss-offunction mutants of Wnt/␤-catenin signaling components (37,50,72). Whether these observations are due to cross talk of Wnt/␤-catenin and sex steroid signaling pathways or related to sexually dimorphic bone mass accrual, bone turnover, and/or osteocyte mechanotransduction (3,41,59,72) is currently unknown and remains to be addressed by future studies.…”

Expression of the Hutchinson-Gilford Progeria Mutation during Osteoblast Development Results in Loss of Osteocytes, Irregular Mineralization, and Poor Biomechanical Properties

“…The Impact of Bone-specific Progerin Expression on DNA Damage Response-To test for changes in Wnt signaling, which has previously been seen in HGPS, we found that the lymphoid enhancer-binding factor (Lef1), which is a Wnt-regulated transcription factor known to regulate osteoblast maturation (35), was significantly reduced in our mouse model. Furthermore, when HGPS mice were compared with wild-type animals, we saw an overall trend toward the lower expression for most of the studied target genes, including Cdkn1a, Jag1, Jag2, Hes1, and Tcf3 (Fig.…”