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

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 8

Impairment of EP4 sensory nerves promotes adipogenesis and attenuates bone regeneration.

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Impairment of EP4 sensory nerves promotes adipogenesis and attenuates bo...
(A and B) Representative μCT images of bone regeneration 7 days after femoral bone marrow ablation in 3-month-old male LepR-Cre;YFP mice treated with capsaicin (30 mg/kg/d) or vehicle. Scale bar: 1 mm. Areas selected for measurement of BV/TV are indicated by yellow squares. (C) Representative SO/FG and Masson’s staining (red, muscle and cytoplasm; blue, bone) images in the regeneration area in 3-month-old male LepR-Cre;YFP mice treated with capsaicin or vehicle 7 days after bone marrow ablation. Red represents cartilage area; green represents woven bone area in SO/FG staining. Scale bars: 100 μm. (D–F) Representative images and analysis of perilipin (red) and OCN (green) staining in the regeneration area from the capsaicin-treated and control groups. Scale bar: 50 μm. (G and H) Representative images of immunofluorescence staining of colocalization of perilipin (red) and YFP (representing LepR+ cells; green), and quantitative analysis of density of YFP+ adipocytes in the regeneration area from capsaicin-treated and control groups. Scale bar: 100 μm. (I and J) Representative μCT images of bone regeneration after femoral bone marrow ablation in 3-month-old male EP4WT and EP4Avil–/– mice treated with 10 mg/kg/d SW033291 or vehicle 7 days after bone marrow ablation. Scale bar: 1 mm. Selected areas for the measurements of BV/TV are indicated by yellow squares. (K–M) Immunohistochemical staining and quantitative analysis of perilipin (red) and OCN (green) in the regeneration area from 3-month-old male EP4WT and EP4Avil–/– mice treated with 10 mg/kg/d SW033291 or vehicle. Scale bar: 50 μm. n ≥ 6 per group; *P < 0.05 (Student’s t test for B, E, F, and H; 2-way ANOVA for J–L).