Mutation of the galectin-3 glycan-binding domain (Lgals3-R200S) enhances cortical bone expansion in male mice and trabecular bone mass in female mice.

Abstract

We previously observed that genomic loss of galectin‐3 (Gal‐3; encoded by Lgals3) in mice has a significant protective effect on age‐related bone loss. Gal‐3 has both intracellular and extracellular functionality, and we wanted to assess whether the affect we observed in the Lgals3 knockout (KO) mice could be attributed to the ability of Gal‐3 to bind glycoproteins. Mutation of a highly conserved arginine to a serine in human Gal‐3 (LGALS3‐R186S) blocks glycan binding and secretion. We generated mice with the equivalent mutation (Lgals3‐R200S) and observed a subsequent reduction in Gal‐3 secretion from mouse embryonic fibroblasts and in circulating blood. When examining bone structure in aged mice, we noticed some similarities to the Lgals3‐KO mice and some differences. First, we observed greater bone mass in Lgals3‐R200S mutant mice, as was previously observed in Lgals3‐KO mice. Like Lgals3‐KO mice, significantly increased trabecular bone mass was only observed in female Lgals3‐R200S mice. These results suggest that the greater bone mass observed is driven by the loss of extracellular Gal‐3 functionality. However, the results from our cortical bone expansion data showed a sex‐dependent difference, with only male Lgals3‐KO mice having an increased response, contrasting with our earlier study. These notable sex differences suggest a potential role for sex hormones, most likely androgen signaling, being involved. In summary, our results suggest that targeting extracellular Gal‐3 function may be a suitable treatment for age‐related loss of bone mass.