β-Receptor blocker enhances the anabolic effect of PTH after osteoporotic fracture

IF 14.3 1区 医学 Q1 CELL & TISSUE ENGINEERING Bone Research Pub Date : 2024-03-21 DOI:10.1038/s41413-024-00321-z
Jie Huang, Tong Wu, Yi-Rong Jiang, Xuan-Qi Zheng, Huan Wang, Hao Liu, Hong Wang, Hui-Jie Leng, Dong-Wei Fan, Wan-Qiong Yuan, Chun-Li Song
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Abstract

The autonomic nervous system plays a crucial role in regulating bone metabolism, with sympathetic activation stimulating bone resorption and inhibiting bone formation. We found that fractures lead to increased sympathetic tone, enhanced osteoclast resorption, decreased osteoblast formation, and thus hastened systemic bone loss in ovariectomized (OVX) mice. However, the combined administration of parathyroid hormone (PTH) and the β-receptor blocker propranolol dramatically promoted systemic bone formation and osteoporotic fracture healing in OVX mice. The effect of this treatment is superior to that of treatment with PTH or propranolol alone. In vitro, the sympathetic neurotransmitter norepinephrine (NE) suppressed PTH-induced osteoblast differentiation and mineralization, which was rescued by propranolol. Moreover, NE decreased the PTH-induced expression of Runx2 but enhanced the expression of Rankl and the effect of PTH-stimulated osteoblasts on osteoclastic differentiation, whereas these effects were reversed by propranolol. Furthermore, PTH increased the expression of the circadian clock gene Bmal1, which was inhibited by NE-βAR signaling. Bmal1 knockdown blocked the rescue effect of propranolol on the NE-induced decrease in PTH-stimulated osteoblast differentiation. Taken together, these results suggest that propranolol enhances the anabolic effect of PTH in preventing systemic bone loss following osteoporotic fracture by blocking the negative effects of sympathetic signaling on PTH anabolism.

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β-受体阻滞剂可增强骨质疏松性骨折后 PTH 的合成代谢作用
自律神经系统在调节骨代谢方面起着至关重要的作用,交感神经的激活会刺激骨吸收并抑制骨形成。我们发现,骨折会导致交感神经张力增加、破骨细胞吸收增强、成骨细胞形成减少,从而加速卵巢切除(OVX)小鼠的全身骨质流失。然而,联合使用甲状旁腺激素(PTH)和β受体阻滞剂普萘洛尔能显著促进卵巢切除小鼠全身骨形成和骨质疏松性骨折愈合。这种治疗效果优于单独使用 PTH 或普萘洛尔的治疗。在体外,交感神经递质去甲肾上腺素(NE)抑制了 PTH 诱导的成骨细胞分化和矿化,而普萘洛尔可挽救这种抑制作用。此外,去甲肾上腺素降低了 PTH 诱导的 Runx2 的表达,但增强了 Rankl 的表达以及 PTH 刺激的成骨细胞对破骨细胞分化的影响,而普萘洛尔可逆转这些影响。此外,PTH 增加了昼夜节律钟基因 Bmal1 的表达,而 NE-βAR 信号传导抑制了 Bmal1 的表达。Bmal1 基因敲除阻断了普萘洛尔对 NE 诱导的 PTH 刺激成骨细胞分化下降的挽救作用。综上所述,这些结果表明,普萘洛尔通过阻断交感神经信号对PTH合成代谢的负面影响,增强了PTH在预防骨质疏松性骨折后全身骨丢失方面的合成代谢作用。
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来源期刊
Bone Research
Bone Research CELL & TISSUE ENGINEERING-
CiteScore
20.00
自引率
4.70%
发文量
289
审稿时长
20 weeks
期刊介绍: Established in 2013, Bone Research is a newly-founded English-language periodical that centers on the basic and clinical facets of bone biology, pathophysiology, and regeneration. It is dedicated to championing key findings emerging from both basic investigations and clinical research concerning bone-related topics. The journal's objective is to globally disseminate research in bone-related physiology, pathology, diseases, and treatment, contributing to the advancement of knowledge in this field.
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