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.

自主神经系统在调节骨代谢中起着至关重要的作用，交感神经激活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）小鼠的全身性骨质流失。然而，联合使用甲状旁腺激素（PTH）和β-受体阻滞剂普萘洛尔可显着促进 OVX 小鼠的全身骨形成和骨质疏松性骨折愈合。这种治疗的效果优于单独用PTH或普萘洛尔治疗。在体外，交感神经递质去甲肾上腺素 (NE) 抑制 PTH 诱导的成骨细胞分化和矿化，普萘洛尔可以挽救这一现象。此外，NE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，而这些影响被普萘洛尔逆转。此外，PTH 增加了生物钟基因Bmal1的表达，而该基因被 NE-βAR 信号传导抑制。 Bmal1敲除阻断了普萘洛尔对 NE 诱导的 PTH 刺激的成骨细胞分化减少的拯救作用。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 PTH 的合成代谢作用，从而预防骨质疏松性骨折后的全身性骨质流失。