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

FEBS Open Bio. 2022 Oct;12(10):1717-1728. doi: 10.1002/2211-5463.13483. Epub 2022 Sep 14.


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.

Keywords: CRISPR/Cas9; bone μCT; galectin; genetic animal models; sexual dimorphism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androgens
  • Animals
  • Arginine
  • Cancellous Bone* / growth & development
  • Cortical Bone* / growth & development
  • Female
  • Fibroblasts / metabolism
  • Galectin 3* / genetics
  • Humans
  • Male
  • Mice
  • Mice, Knockout
  • Mutation
  • Polysaccharides
  • Serine / genetics


  • Androgens
  • Galectin 3
  • Lgals3 protein, mouse
  • Polysaccharides
  • Serine
  • Arginine