Canonical Wnt signaling plays a major role in bone development. The transcription factors TCF/LEF are activated in the nucleus in response to Wnt signaling. Preliminary results from our lab have shown that Lef1 heterozygous Lef1 female mice have low bone volume w as compared to wild type females, whereas Lef1 heterozygous males have normal bone volume. Because sex steroids have significant role in bone development, we were interested to know if androgens protected the male mice from bone loss that otherwise occurs as a result of Lef1 haploinsufficiency.

To understand if the androgen signaling actually played a role in protecting Lef1 haploinsufficient males we used Tfm mutant male mice, which have aberrant androgen receptor. Lef1 haploinsufficient male mice were bred with female mice having the Tfm mutation. Bone volume density was assessed in F1 generation male and female mice with Tfm mutation and Lef1 heterozygosity. Using micro computed tomography (μCT), we imaged the distal femurs of 9-20 bones for each of the eight genotypes, and calculated both cortical and trabecular bone parameters.

We observed that our results were consistent with the preliminary data that the bone loss was specific and to female mice. Male mice with Tfm mutation showed bone loss compared to male mice that don't have Tfm mutation. Most importantly, comparison of Lef1+/- with Lef1+/+ male mice on a Tfm mutant background showed bone loss as a result of Lef1 haploinsufficiency, although the p value was only marginally significant (p<0.059). Hence we conclude that there is an interaction between Lef1 and androgen signaling in bone development.