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

Abstract

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; E2), 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 ± E2 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. E2 rescue more strongly increased B.Ar in Lgals3-KO compared to wild-type female mice due to a failure of E2 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 E2 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.

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Acknowledgements

We thank the members of the Williams laboratory at VARI for their assistance; David Nadziejka for assistance in preparing the manuscript; Lisa Turner, Carrie Joynt, and the rest of the VARI histology core for their histology work; and VARI’s vivarium staff for outstanding animal husbandry. This project was funded by Van Andel Research Institute and Van Andel Institute Graduate School, Grand Rapids, MI.

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KAM designed the study, performed the surgeries and analyses, and drafted the manuscript. DD and JL contributed to the experimental work. BOW oversaw the study, provided critical guidance, and was a major contributor to manuscript revisions. All authors critically reviewed the manuscript and approved the final version. All authors agree to be accountable for the work and to ensure that any questions relating to the accuracy and integrity of the paper are investigated and properly resolved.

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Correspondence to Bart O. Williams.

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Conflict of Interest

Authors Kevin A. Maupin, Daniel Dick, Johan Lee, and Bart O. Williams have declared no conflicts of interest associated with this study. BOW has served as a consultant for Amgen, is an Advisory Board member at Surrozen, and has research support from Janssen in areas unrelated to this study.

Human and Animal Rights

All animal procedures were carried out in compliance with the regulations and guidelines set by the Institutional Animal Care and Use Committee at VARI. The protocols used were approved by the Institutional Animal Care and Use Committee at VARI prior to the initiation of experiments.

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Maupin, K.A., Dick, D., Lee, J. et al. Loss of Lgals3 Protects Against Gonadectomy-Induced Cortical Bone Loss in Mice. Calcif Tissue Int 106, 283–293 (2020). https://doi.org/10.1007/s00223-019-00630-0

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Keywords

  • Genetic animal models
  • Sex steroids
  • Bone µCT
  • Bone histomorphometry
  • Galectin