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Sensory nerves regulate mesenchymal stromal cell lineage commitment by tuning sympathetic tones
Bo Hu, … , Wen Yuan, Xu Cao
Bo Hu, … , Wen Yuan, Xu Cao
Published March 19, 2020
Citation Information: J Clin Invest. 2020;130(7):3483-3498. https://doi.org/10.1172/JCI131554.
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Research Article Bone biology Article has an altmetric score of 9

Sensory nerves regulate mesenchymal stromal cell lineage commitment by tuning sympathetic tones

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Abstract

The sensory nerve was recently identified as being involved in regulation of bone mass accrual. We previously discovered that prostaglandin E2 (PGE2) secreted by osteoblasts could activate sensory nerve EP4 receptor to promote bone formation by inhibiting sympathetic activity. However, the fundamental units of bone formation are active osteoblasts, which originate from mesenchymal stromal/stem cells (MSCs). Here, we found that after sensory denervation, knockout of the EP4 receptor in sensory nerves, or knockout of COX-2 in osteoblasts, could significantly promote adipogenesis and inhibit osteogenesis in adult mice. Furthermore, injection of SW033291 (a small molecule that locally increases the PGE2 level) or propranolol (a beta blocker) significantly promoted osteogenesis and inhibited adipogenesis. This effect of SW033291, but not propranolol, was abolished in conditional EP4-KO mice under normal conditions or in the bone repair process. We conclude that the PGE2/EP4 sensory nerve axis could regulate MSC differentiation in bone marrow of adult mice.

Authors

Bo Hu, Xiao Lv, Hao Chen, Peng Xue, Bo Gao, Xiao Wang, Gehua Zhen, Janet L. Crane, Dayu Pan, Shen Liu, Shuangfei Ni, Panfeng Wu, Weiping Su, Xiaonan Liu, Zemin Ling, Mi Yang, Ruoxian Deng, Yusheng Li, Lei Wang, Ying Zhang, Mei Wan, Zengwu Shao, Huajiang Chen, Wen Yuan, Xu Cao

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Figure 4

Deletion of the EP4 receptor in sensory nerves promotes adipogenesis and inhibits osteogenesis.

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Deletion of the EP4 receptor in sensory nerves promotes adipogenesis and...
(A–C) Representative μCT images of femurs from 1- and 3-month-old male EP4WT and EP4Avil–/– mice. The thin yellow lines indicate the area where the cross-section images were captured (0.5 mm proximal from the growth plate). Quantitative analysis of Tb.BV/TV and Tb.Th. Scale bar: 1 mm. (D–F) Representative μCT-detected OsO4-stained images of decalcified femurs and quantitative analysis of Ad.N and Ad.V/Ma.V in distal femurs from 3-month-old male EP4WT and EP4Avil–/– mice. Scale bar: 500 μm. (G–I) Immunohistochemical staining of perilipin (red) and OCN (green) in femurs from 3-month-old male EP4WT and EP4Avil–/– mice treated with SW033291 (10 mg/kg/d) or vehicle for 1 month. Quantitative analysis of the density of perilipin and OCN in femurs from 3-month-old male EP4WT and EP4Avil–/– mice treated with SW033291 or vehicle for 1 month. Scale bar: 50 μm. (J–M) Representative images of crystal violet–stained CFU-F, oil red O–stained CFU-AD, and alizarin red S–stained CFU-OB. Quantitative analysis of CFU-F, CFU-AD, and CFU-OB MSCs isolated from 3-month-old male EP4WT and EP4Avil–/– mice. (N–Q) Representative dot plot images of flow cytometry and quantitative analysis of CD45–CD31–Sca-1+CD24– APCs, CD45–CD31–Sca-1–Pα+ OPCs, and CD45–CD31–Sca-1+CD24+ MSCs of live cells isolated from femurs of 3-month-old male EP4WT and EP4Avil–/– mice. n ≥ 6 per group; *P < 0.05 (Student’s t test; 2-way ANOVA for H and I).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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