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Osteocyte-specific WNT1 regulates osteoblast function during bone homeostasis
Kyu Sang Joeng, … , Catherine Ambrose, Brendan H. Lee
Kyu Sang Joeng, … , Catherine Ambrose, Brendan H. Lee
Published June 19, 2017
Citation Information: J Clin Invest. 2017;127(7):2678-2688. https://doi.org/10.1172/JCI92617.
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Research Article Bone biology Genetics Article has an altmetric score of 7

Osteocyte-specific WNT1 regulates osteoblast function during bone homeostasis

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Abstract

Mutations in WNT1 cause osteogenesis imperfecta (OI) and early-onset osteoporosis, identifying it as a key Wnt ligand in human bone homeostasis. However, how and where WNT1 acts in bone are unclear. To address this mechanism, we generated late-osteoblast-specific and osteocyte-specific WNT1 loss- and gain-of-function mouse models. Deletion of Wnt1 in osteocytes resulted in low bone mass with spontaneous fractures similar to that observed in OI patients. Conversely, Wnt1 overexpression from osteocytes stimulated bone formation by increasing osteoblast number and activity, which was due in part to activation of mTORC1 signaling. While antiresorptive therapy is the mainstay of OI treatment, it has limited efficacy in WNT1-related OI. In this study, anti-sclerostin antibody (Scl-Ab) treatment effectively improved bone mass and dramatically decreased fracture rate in swaying mice, a model of global Wnt1 loss. Collectively, our data suggest that WNT1-related OI and osteoporosis are caused in part by decreased mTORC1-dependent osteoblast function resulting from loss of WNT1 signaling in osteocytes. As such, this work identifies an anabolic function of osteocytes as a source of Wnt in bone development and homoeostasis, complementing their known function as targets of Wnt signaling in regulating osteoclastogenesis. Finally, this study suggests that Scl-Ab is an effective genotype-specific treatment option for WNT1-related OI and osteoporosis.

Authors

Kyu Sang Joeng, Yi-Chien Lee, Joohyun Lim, Yuqing Chen, Ming-Ming Jiang, Elda Munivez, Catherine Ambrose, Brendan H. Lee

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Figure 1

The phenotypes of bone-specific Wnt1 loss-of-function (Dmp1-Cre Wnt1fl/fl) mouse models.

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The phenotypes of bone-specific Wnt1 loss-of-function (Dmp1-Cre Wnt1fl/f...
(A) X-ray radiograph and micro-CT (μCT) images of female WT and Dmp1-Cre Wnt1fl/fl mice at 2 months old. The white arrow indicates a fracture site in the mutant mouse. (B) Quantification results of μCT analysis; femoral trabecular bone for bone volume/total volume (BV/TV), trabecular number (Tb.N), trabecular thickness (Tb.Th), and trabecular space (Tb.Sp), and cortical bone for cortical thickness (Cort.Th). Results are shown as means ± SD (n = 8 per group). (C) Histomorphometric analysis of L4 vertebrae; osteoclast numbers per bone surface (N.Oc/BS), osteoblast numbers per bone surface (N.Ob/BS), mineral surface per bone surface (MS/BS), mineral apposition rate (MAR), and bone formation rate (BFR) in WT and Dmp1-Cre Wnt1fl/fl mice. Results are shown as means ± SD (n = 6 for WT, n = 8 for Dmp1-Cre Wnt1fl/fl). The comparison between WT and Wnt1 loss-of-function mice is determined by Student’s t test. **P < 0.01, ***P < 0.001.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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