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

Osteocyte-specific WNT1 regulates osteoblast function during bone homeostasis

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 3

mTORC1 signaling mediated enhanced osteoblast differentiation and mineralization by Wnt1 overexpression in vitro.

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mTORC1 signaling mediated enhanced osteoblast differentiation and minera...
(A) Quantitative reverse transcriptase PCR (RT-PCR) of Wnt1, Runx2, alkaline phosphatase, and osteocalcin in control helper-dependent adenovirus–treated (HDAd-GFP) and WNT1 helper-dependent adenovirus–treated (HDAd-mWnt1) ST2 cells. Results are shown as fold change of the mean of control group ± SD (n = 3 per group). (B) Mineralization assay by alizarin red staining on the seventh day after control virus–treated and HDAd-mWnt1–treated ST2 cells. (C) The representative Western blot analysis showed activated pS6 relative to total S6 and pAkt (Ser473) relative to total Akt of control virus– and HDAd-mWnt1–treated ST2 cells. Results are shown as fold change of the mean of control group ± SD (n = 3 per group). The Western blot represents 3 individual experiments. (D and E) Quantitative RT-PCR of alkaline phosphatase (D) and Lef1 (E) after control treatment (DMSO) or pharmacological inhibition of mTOR signaling by rapamycin in control virus– and HDAd-mWnt1–treated ST2 cells. Results are shown as fold change of the mean of control group ± SD (n = 3 per group). (F) Mineralization assay after control treatment (DMSO) or pharmacological inhibition of mTOR signaling by rapamycin in control virus– and HDAd-mWnt1–treated ST2 cells. The comparison between control and HDAd-mWnt1–treated groups is determined by Student’s t test. *P < 0.05, **P < 0.01, ***P < 0.001.