Journal
JOURNAL OF BONE AND MINERAL RESEARCH
Volume 37, Issue 1, Pages 108-120Publisher
WILEY
DOI: 10.1002/jbmr.4445
Keywords
BIOMECHANICS; GENETIC ANIMAL MODELS; OSTEOBLASTS; WNT; BETA-CATENIN; LRPS; PARACRINE PATHWAYS
Categories
Funding
- NIH [R01 AR047867, T32 AR060719]
- Washington University Musculoskeletal Research Center [P30 AR074992]
- [P30 CA91842]
- [UL1 TR002345]
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The secretion of Wnt ligands is essential for adult bone homeostasis, and inhibiting their secretion results in decreased bone formation and increased resorption. Additionally, osteoblast-derived Wnts play a crucial role in mediating the bone anabolic response to tibial loading.
Wnt signaling is critical to many aspects of skeletal regulation, but the importance of Wnt ligands in the bone anabolic response to mechanical loading is not well established. Recent transcriptome profiling studies by our laboratory and others show that mechanical loading potently induces genes encoding Wnt ligands, including Wnt1 and Wnt7b. Based on these findings, we hypothesized that mechanical loading stimulates adult bone formation by inducing Wnt ligand expression. To test this hypothesis, we inhibited Wnt ligand secretion in adult (5 months old) mice using a systemic (drug) and a bone-targeted (conditional gene knockout) approach, and subjected them to axial tibial loading to induce lamellar bone formation. Mice treated with the Wnt secretion inhibitor WNT974 exhibited a decrease in bone formation in non-loaded bones as well as a 54% decline in the periosteal bone formation response to tibial loading. Next, osteoblast-specific Wnt secretion was inhibited by dosing 5-month-old Osx-CreERT2; Wls(F/F) mice with tamoxifen. Within 1 to 2 weeks of Wls deletion, skeletal homeostasis was altered with decreased bone formation and increased resorption, and the anabolic response to loading was reduced 65% compared to control (Wls(F/F)). Together, these findings show that Wnt ligand secretion is required for adult bone homeostasis, and furthermore establish a role for osteoblast-derived Wnts in mediating the bone anabolic response to tibial loading. (c) 2021 American Society for Bone and Mineral Research (ASBMR).
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