We recently reported, based on RNAseq, that Wnt1 and Wnt7b were two of only eight transcripts significantly upregulated in cortical bone 4 h after 1, 3 and 5 daily bouts of axial tibial loading in 5-mo old mice ( Chermside-Scabbo et al., 2020). used RNAseq and identified Wnt1, Wnt7b and Wnt10b as genes elevated early after axial tibial loading ( Kelly et al., 2016), findings corroborated by others ( Galea et al., 2017 Holguin et al., 2016). assayed several Wnt-related genes and reported elevated Wnt10b expression 4 h after loading ( Robinson et al., 2006). Reports by several groups demonstrate that loading induces the expression of Wnt genes in bones of mice. While it is well known that Wnt pathway activation is initiated by the binding of one of 19 Wnt ligands to Frizzled and Lrp5/6 cell surface co-receptors ( Clevers & Nusse, 2012), the role of Wnt ligands in the anabolic response to loading has not been well described. The Wnt co-receptor LRP5 is required for the response to loading ( Sawakami et al., 2006), and loading-induced downregulation of the Wnt antagonists Sclerostin (Sost) and Dkk1 favors bone formation ( Lara-Castillo et al., 2015 Robling et al., 2008 Tu et al., 2012). Mechanical loading is a potent stimulus for bone formation, mediated in part by the Lrp/Wnt signaling pathway ( Robinson et al., 2006). These findings establish a requirement for Wnt ligand secretion by osteoblasts for adult bone homeostasis and the anabolic response to mechanical loading. Similarly, within 1-2 weeks of Wls deletion in osteoblasts (Osx-CreERT2 Wls F/F mice), 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). Mice treated with the porcupine inhibitor WNT974 exhibited a decrease in bone formation in non-loaded limbs as well as a 54% decline in the periosteal bone formation response to tibial loading. We inhibited Wnt ligand secretion in adult (5-mo) mice using a systemic (drug) and a bone-targeted (genetic) approach, and subjected them to axial tibial loading to induce lamellar bone formation. Wnt signaling is critical to many aspects of skeletal regulation, but the importance of Wnt ligands in adult bone homeostasis and the anabolic response to mechanical loading is not well documented.
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