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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.
摘要：
自主神经系统在调节骨代谢中起着至关重要的作用,与交感神经激活刺激骨吸收和抑制骨形成。我们发现骨折导致交感神经紧张增加，增强破骨细胞吸收，成骨细胞形成减少，因此加速了卵巢切除(OVX)小鼠的全身性骨丢失。然而,甲状旁腺激素（PTH）和β受体阻滞剂普萘洛尔的联合给药可显著促进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使用PTH或普萘洛尔的治疗。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，被普萘洛尔救出.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，而普萘洛尔逆转了这些作用。此外，PTH增加了昼夜节律时钟基因Bmal1的表达，该基因被NE-βAR信号抑制。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降低的挽救作用。一起来看,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预防骨质疏松性骨折后全身性骨丢失的合成代谢作用.
