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.
Highlights
The wingless/Wnt family of secreted glycoproteins has critical roles in cell growth and differentiation, and is highly conserved among vertebrates, flies, and primitive multicellular organisms [1,2]
The decrease in BV/TV due to lymphoid enhancer factor 1 (Lef1) haploinsufficiency resembles the magnitude of trabecular bone loss due to Lipoprotein Receptor-Related Protein 6 (Lrp6) haploinsufficiency [24]
While the decreased BV/TV at the vertebral bodies was attributable to thinning of trabeculae, the low bone mass (LBM) at the distal femoral metaphysis was due to decreased trabecular number (Tb.N) and was associated with decreased connectivity density (Conn.D, Figure 1)
Summary
The wingless/Wnt family of secreted glycoproteins has critical roles in cell growth and differentiation, and is highly conserved among vertebrates, flies, and primitive multicellular organisms [1,2]. Wnt ligands bind to membrane complexes consisting of a seven transmembrane domain receptor of the frizzled family [3,4,5] and a ‘single-pass’ co-receptor, Lipoprotein Receptor-Related Protein 6 (Lrp6) and possibly Lrp as well [6,7,8]. In the absence of stimulation, the Wnt pathway is under the negative control of a pair of protein-serine kinases, Glycogen Synthase Kinase 3a and 3b (Gsk3a, Gsk3b), which phosphorylate b-catenin, a Wnt transducer, resulting in its ubiquitination and subsequent proteasomal degradation [9,10]. B-catenin accumulates and translocates to the nucleus, where it activates Wnt target genes by associating with the DNA-binding HMG box transcription factors lymphoid enhancer factor 1 (Lef1), T-cell factor 7 (Tcf7), Tcf7L1, and/or Tcf7L2 [12,13,14,15]. Tcf7L1 and Tcf7L2 are commonly known as Tcf, Tcf, and Tcf, respectively, and these common names are used in this paper
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