Background

Reduced serum estrogen levels in postmenopausal patients not only aggravate bone loss but also impact myokine secretion. Emerging evidence has revealed the importance of myokines in bone metabolism, and exercise can interfere with the secretion of myokines. However, few studies have explored the impact of exercise on myokine secretion in the postmenopausal osteoporosis (PMOP) process.

Methods

Ten-weeks-old C57B/L6 female mice were used for constructing the postmenopausal osteoporosis model. The expression levels of kynurenine aminotransferases (Kats) were detected by RT-PCR and Western Blot. The concentration of serum kynurenic acid (Kyna) was detected by HPLC-MS. Micro-CT analysis was used for determine the changes of bone mineral density and the microstructure. The primary osteoblast and osteoclast were isolated from mice to determine the effect and mechanism of Kyna on the bone formation and resorption.

Results

In our research, we found a lower serum level of muscle-derived kynurenic acid (Kyna) in PMOP model mice, accompanied by a decreased level of kynurenine aminotransferases (Kats) in the gastrocnemius muscle. Moreover, treadmill-running exercise upregulated the muscle levels of KATs and increased the serum concentration of Kyna, which was positively correlated with the alleviation of bone loss. Furthermore, we found that exogenous Kyna treatment alleviated bone mineral loss and microstructure destruction in PMOP mice by inhibiting osteoclast maturation and increasing osteoblast viability. Mechanistically, we observed that Kyna reduced the NFκB p65 phosphorylation level by activating the Gpr35 receptor, which inhibited NFATc1 expression in osteoclasts and upregulated Runx2 expression in osteoblasts.

Conclusion

Our results revealed that the muscle levels of Kats and serum level of Kyna were negatively correlated with the severity of PMOP. Exercise intervention and exogenous Kyna treatment alleviated the impairment of bone microstructure through the Gpr35 receptor, paving the way for a novel therapeutic intervention in PMOP.

The Translational potential of this article

This study provides evidences that Kyna could increase the osteoblastgenesis and inhibit the osteoclastgenesis, which could be a novel therapeutic approach for osteoporosis treatment.

中文翻译：

---

运动通过 Gpr35/NFκB p65 通路加速骨骼肌中肌肉源性犬尿酸的产生并缓解绝经后骨质疏松症

背景

绝经后患者血清雌激素水平降低不仅会加剧骨质流失，还会影响肌因子的分泌。新出现的证据表明肌动蛋白在骨代谢中的重要性，运动会干扰肌动蛋白的分泌。然而，很少有研究探讨运动对绝经后骨质疏松症 (PMOP) 过程中肌动蛋白分泌的影响。

方法

10周龄C57B/L6雌性小鼠用于构建绝经后骨质疏松模型。通过RT-PCR和Western Blot检测犬尿氨酸氨基转移酶（Kats）的表达水平。通过HPLC-MS检测血清犬尿酸(Kyna)的浓度。显微CT分析用于确定骨矿物质密度和微观结构的变化。从小鼠中分离出原代成骨细胞和破骨细胞，以确定Kyna对骨形成和骨吸收的影响和机制。

结果

在我们的研究中，我们发现 PMOP 模型小鼠血清中肌源性犬尿酸 (Kyna) 水平较低，同时腓肠肌中犬尿氨酸氨基转移酶 (Kats) 水平降低。此外，跑步机跑步运动上调了 KATs 的肌肉水平并增加了 Kyna 的血清浓度，这与缓解骨质流失呈正相关。此外，我们发现外源性 Kyna 治疗通过抑制破骨细胞成熟和增​​加成骨细胞活力来减轻 PMOP 小鼠的骨矿物质损失和微结构破坏。从机制上讲，我们观察到 Kyna 通过激活 Gpr35 受体降低 NFκB p65 磷酸化水平，从而抑制破骨细胞中 NFATc1 的表达并上调成骨细胞中 Runx2 的表达。

结论

我们的研究结果表明，Kats 的肌肉水平和 Kyna 的血清水平与 PMOP 的严重程度呈负相关。运动干预和外源性 Kyna 治疗通过 Gpr35 受体减轻了骨微结构的损害，为 PMOP 的新型治疗干预铺平了道路。

本文的转化潜力

本研究提供的证据表明，Kyna 可以增加成骨细胞生成并抑制破骨细胞生成，这可能是治疗骨质疏松症的一种新的治疗方法。