Loss of Lgals3 Protects Against Gonadectomy-Induced Cortical Bone Loss in Mice

Sex hormone deprivation commonly occurs following menopause in women or after androgen-depletion during prostate cancer therapy in men, resulting in rapid bone turnover and loss of bone mass. There is a need to identify novel therapies to improve bone mass in these conditions. Previously, we identified age- and sex-dependent effects on bone mass in mice with deletion of the gene encoding the β-galactoside binding lectin, galectin-3 ( Lgals3 -KO). Due to the influence of sex on the phenotype, we tested the role of sex hormones, estrogen (β-estradiol; E 2 ), and androgen (5α-dihydroxytestosterone; DHT) in Lgals3 -KO mice. To address this, we subjected male and female wild-type and Lgals3 -KO mice to gonadectomy ± E 2 or DHT rescue and compared differential responses in bone mass and bone formation. Following gonadectomy, male and female Lgals3 -KO mice had greater cortical bone expansion (increased total area; T.Ar) and reduced loss of bone area (B.Ar). While T.Ar and B.Ar were increased in response to DHT in wild-type mice, DHT did not alter these parameters in Lgals3 -KO mice. E 2 rescue more strongly increased B.Ar in Lgals3 -KO compared to wild-type female mice due to a failure of E 2 to repress the increase in T.Ar following gonadectomy. Lgals3 -KO mice had more osteoblasts relative to bone surface when compared to wild-type animals in sham, gonadectomy, and E 2 rescue groups. DHT suppressed this increase. This study revealed a mechanism for the sex-dependency of the Lgals3 -KO aging bone phenotype and supports targeting galectin-3 to protect against bone loss associated with decreased sex hormone production.