An imbalance between bone formation and bone resorption, which occurs due to aging or sex-hormone deprivation, results in decreased bone mass and an increased risk of fracture. Previous studies of the β-galactoside binding lectin, galectin-3 (Lgals3), have suggested that galectin-3 may be involved in bone remodeling. To answer whether galectin-3 regulates bone remodeling, we compared bone parameters of mice with global deletion of the Lgals3 gene (Lgals3-KO and Lgals3-Δ), osteoblast conditional deletion (OCN-cre; Lgals3-flox), and a mutation to disrupt glycan binding of galectin-3 (Lgals3-R200S) in aged mice and following gonadectomy in Lgals3-KO mice. These models showed increased cortical bone expansion in Lgals3-deficient mice, with preserved or enhanced bone mass. Despite improved cortical geometry, mechanical testing revealed reductions in the quality of bone from Lgals3-deficient mice. Related to this, we observed increased osteoid and abnormal collagen fibril structure in Lgals3-KO bones.
The loss of Lgals3 resulted in increased osteoblast formation both in vivo and in vitro. Osteoclast formation and function was generally unaffected. Lgals3-deficient mice were not osteopetrotic, which could be explained by reduced Opg/Rankl ratios. These effects are consistent with galectin-3 functioning as a regulator of bone remodeling.
Our studies suggest that disruption of galectin-3 may be useful for treatment of bone loss, although more work needs to be done to determine how the bone matrix changes in Lgals3-KO mice. Due to the numerous signaling pathways that are influenced by galectin-3, we were not able to identify a clear molecular mechanism. However, we did uncover a potential role for galectin-3 in the regulation of sex-hormone bioavailability. In addition, the creation of the new Lgals3-R200S mouse revealed that loss of extracellular galectin-3 was the primary driver of increased bone mass in Lgals3 -KO mice and will be a valuable tool for dissecting the intracellular vs. extracellular roles of galectin-3.
|Commitee:||Melcher, Karsten, Robling, Alex, Turner, Julie, Wang, John, Yang, Tao|
|School:||Van Andel Research Institute|
|School Location:||United States -- Michigan|
|Source:||DAI-B 78/11(E), Dissertation Abstracts International|
|Subjects:||Genetics, Aging, Physiology|
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