Gong Yan, Zhang Yuzhuo, Chen Xingda, Zhou Zelin, Qin Weicheng, Gan Yanchi, He Jiahui, Ma Jizhi, Chen Guifeng, Shang Qi, Tang Kai, Chen Honglin, Liu Yu, Liang De, Shen Gengyang, Jiang Xiaobing, Cheng Zhaojun
Trauma and Orthopaedics Center, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.
Department of Traditional Chinese Medicine, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
Front Pharmacol. 2025 Apr 1;16:1517221. doi: 10.3389/fphar.2025.1517221. eCollection 2025.
The origin of intervertebral disc degeneration (IDD) is highly complex, where both cartilage endplate remodeling and vertebral osteoporosis are of utmost importance. Myristic acid (MA), a saturated fatty acid derived from nutmeg, a traditional Chinese herb, has been shown to boost memory. Additionally, its isomers have been verified to have anti-osteoporotic characteristics. However, the precise mechanism by which MA functions in relation to IDD remains unclear.
, a naturally aged animal model was used. The drug-administration method of MA was intraperitoneal injection to mice aged 22 months at a dose of 2 mg/kg·d for 2 months. Micro-CT observed vertebral bone mass and endplate changes, followed by Hematoxylin‒eosin (H&E), Masson, and Safranin-O staining of tissues. TRAP staining counted osteoclasts; immunohistochemistry detected the expressions of Aggrecan and Collagen II. Bioinformatics explored MA's anti-IDD mechanism. , MA-treated senescent endplate chondrocytes (induced by TBHP) were analyzed by RT-qPCR and immunofluorescence (IF) for senescence and matrix synthesis markers. TRAP and F-actin detected MA's effect on RAW264.7 osteoclast differentiation (induced by RANKL); qPCR examined the expressions of osteoclast genes.
Using the naturally aged model, we found that MA tended to improve vertebral osteoporosis and endplate osteochondral remodeling, decreased the TRAP activity of the endplate, and alleviated IDD in naturally aged mice. Bioinformatics analysis suggested that the relationships among IDD, osteoporosis, and endplate degeneration were mainly linked to cellular senescence. , MA postponed the senescence of TBHP-induced endplate chondrocytes by increasing the expression of Aggrecan and decreasing the expressions of MMP-3, MMP-9, and the senescence markers p16 and p21. Additionally, MA notably inhibited osteoclast activity, as evidenced by a decrease in the number of osteoclasts and a significant suppression of F-actin formation. At the molecular level, MA efficiently reduced the expressions of osteoclast marker genes like ACP-5, CTSK, and DC-STAMP.
The findings of this research suggest that MA is capable of inhibiting endplate osteochondral remodeling and vertebral osteoporosis, diminishing osteoclastogenesis to preserve bone mass, and consequently delaying IDD in naturally aged mice. Hence, MA holds the potential to serve as an alternative therapeutic approach for IDD.
椎间盘退变（IDD）的起源极为复杂，其中软骨终板重塑和椎体骨质疏松都至关重要。肉豆蔻酸（MA）是一种源自传统中药肉豆蔻的饱和脂肪酸，已被证明能增强记忆力。此外，其异构体已被证实具有抗骨质疏松特性。然而，MA在IDD中的具体作用机制仍不清楚。
采用自然衰老动物模型。MA的给药方法是对22月龄小鼠腹腔注射，剂量为2mg/kg·d，持续2个月。显微CT观察椎体骨量和终板变化，随后对组织进行苏木精-伊红（H&E）、Masson和番红O染色。抗酒石酸酸性磷酸酶（TRAP）染色计数破骨细胞；免疫组化检测聚集蛋白聚糖和胶原蛋白II的表达。生物信息学探索MA的抗IDD机制。对MA处理过的衰老终板软骨细胞（由叔丁基过氧化氢诱导）进行逆转录定量聚合酶链反应（RT-qPCR）和免疫荧光（IF）分析以检测衰老和基质合成标志物。TRAP和F-肌动蛋白检测MA对RAW264.7破骨细胞分化（由核因子κB受体活化因子配体诱导）的影响；qPCR检测破骨细胞基因的表达。
使用自然衰老模型，我们发现MA倾向于改善椎体骨质疏松和终板骨软骨重塑，降低终板的TRAP活性，并减轻自然衰老小鼠的IDD。生物信息学分析表明，IDD、骨质疏松和终板退变之间的关系主要与细胞衰老有关。此外，MA通过增加聚集蛋白聚糖的表达，降低基质金属蛋白酶-3（MMP-3）、基质金属蛋白酶-9（MMP-9）以及衰老标志物p16和p21的表达，延缓了叔丁基过氧化氢诱导的终板软骨细胞衰老。此外，MA显著抑制破骨细胞活性，可以通过破骨细胞数量减少和F-肌动蛋白形成的显著抑制来证明。在分子水平上，MA有效降低了破骨细胞标志物基因如抗酒石酸酸性磷酸酶5（ACP-5）、组织蛋白酶K（CTSK）和树突状细胞特异性跨膜蛋白（DC-STAMP）的表达。
本研究结果表明，MA能够抑制终板骨软骨重塑和椎体骨质疏松，减少破骨细胞生成以维持骨量，从而延缓自然衰老小鼠的IDD。因此MA有潜力作为IDD的一种替代治疗方法。
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