Increased Wnt/β-catenin signaling contributes to autophagy inhibition resulting from a dietary magnesium deficiency in injury-induced osteoarthritis.
Increased Wnt/β-catenin signaling contributes to autophagy inhibition resulting from a dietary magnesium deficiency in injury-induced osteoarthritis.
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Wnt/β-连环蛋白信号传导增加有助于损伤引起的骨关节炎中膳食镁缺乏导致的自噬抑制
DOI：
10.1186/s13075-022-02848-0
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发表时间：
2022-07-08
影响因子：
4.9
通讯作者：
中科院分区：
文献类型：
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作者：
现代饮食中常见的膳食镁缺乏与骨关节炎（OA）易感性有关。尽管存在这种临床关联，但没有研究表明膳食镁缺乏是否会加速OA的发展，特别是在分子水平上。本研究旨在探讨膳食镁缺乏对损伤性OA模型小鼠软骨损伤的加重作用，并探讨其机制。将12周龄损伤性OA模型C57BL/6J小鼠随机分为日推荐镁含量500 mg/kg组和低镁含量100、300 mg/kg组。使用OARSI评分评估关节软骨损伤。为了确定体外分子机制，将小鼠软骨细胞用低镁条件下的0.1和0.4 mM培养基处理，并与正常镁条件下的0.7 mM作为对照。采用实时荧光定量PCR和免疫印迹技术分析合成代谢和分解代谢因子、自噬标志物、β-catenin、Wnt配体和镁通道瞬时受体电位阳离子通道亚家族成员7 （TRPM7）。荧光显微镜DALGreen染色检测自噬体，透射电镜检测自噬体。采用免疫组化方法对小鼠软骨组织中自噬标志物β-catenin和TRPM7进行了体内检测，并对缺镁和正常饮食进行了比较。膳食镁缺乏加重了损伤性软骨损伤，OARSI评分显著升高。低镁饮食小鼠和低镁处理的软骨细胞的自噬标志物LC3-II和Beclin-1均降低。在低镁条件下，自溶酶体和自噬体的数量也减少。此外，镁缺乏导致软骨细胞合成代谢降低，分解代谢增强，而自噬激活剂雷帕霉素可使其恢复。此外，低镁条件下自噬的减少是由激活的Wnt/β-catenin信号介导的。低镁饮食小鼠中TRPM7的表达也下降，表明下游的变化可以通过该通道调节。膳食镁缺乏有助于OA的发展，这是通过Wnt/β-catenin信号激活减少自噬介导的。这些发现表明，对于OA患者或OA高危人群来说，饮食中摄入足够的镁具有潜在的益处。在线版本包含补充材料，可在10.1186/s13075-022-02848-0获得。
Dietary magnesium deficiency, which is common in modern diet, has been associated with osteoarthritis (OA) susceptibility. Despite this clinical association, no study has addressed if dietary magnesium deficiency accelerates OA development, especially at molecular level. This study aimed to explore aggravating effects of dietary magnesium deficiency on cartilage damage in an injury-induced murine OA model and to determine the underlying mechanism. Twelve-week-old C57BL/6J mice subject to injury-induced OA modeling were randomized into different diet groups in which the mice were fed a diet with daily recommended magnesium content (500 mg/kg) or diets with low magnesium content (100 or 300 mg/kg). Articular cartilage damage was evaluated using the OARSI score. To determine molecular mechanisms in vitro, mouse chondrocytes were treated with media of low magnesium conditions at 0.1 and 0.4 mM, compared with normal magnesium condition at 0.7 mM as control. Anabolic and catabolic factors, autophagy markers, β-catenin, Wnt ligands, and a magnesium channel transient receptor potential cation channel subfamily member 7 (TRPM7) were analyzed by quantitative real-time PCR and immunoblotting. Autolysosomes were detected by DALGreen staining via fluorescence microscopy and autophagosomes were evaluated by transmission electron microscopy. Autophagy markers, β-catenin, and TRPM7 were assessed in vivo in the mouse cartilage, comparing between dietary magnesium deficiency and normal diet, by immunohistochemistry. Dietary magnesium deficiency aggravated injury-induced cartilage damage, indicated by significant higher OARSI scores. Autophagy markers LC3-II and Beclin-1 were decreased both in low magnesium diet-fed mice and low magnesium-treated chondrocytes. The number of autolysosomes and autophagosomes was also reduced under low magnesium conditions. Moreover, magnesium deficiency induced decreased anabolic and increased catabolic effect of chondrocytes which could be restored by autophagy activator rapamycin. In addition, reduced autophagy under low magnesium conditions is mediated by activated Wnt/β-catenin signaling. The expression of TRPM7 also decreased in low magnesium diet-fed mice, indicating that downstream changes could be regulated through this channel. Dietary magnesium deficiency contributes to OA development, which is mediated by reduced autophagy through Wnt/β-catenin signaling activation. These findings indicated potential benefits of adequate dietary magnesium for OA patients or those individuals at high risk of OA. The online version contains supplementary material available at 10.1186/s13075-022-02848-0.
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影响因子：
--
作者：
Barde MP;Barde PJ
通讯作者：
Barde PJ
自噬在骨关节炎中的作用
影响因子：
5.5
作者：
Duan R;Xie H;Liu ZZ
通讯作者：
Liu ZZ
影响因子：
7
作者：
Lee, C. H.;Wen, Z. H.;Jean, Y. H.
通讯作者：
Jean, Y. H.
DOI：
10.1016/j.bbrc.2019.03.178
发表时间：
2019-05-21
影响因子：
3.1
作者：
Castiglioni, Sara;Romeo, Valentina;Maier, Jeanette A. M.
通讯作者：
Maier, Jeanette A. M.
影响因子：
5.5
作者：
Herencia, Carmen;Encarnacion Rodriguez-Ortiz, M.;Almaden, Yolanda
通讯作者：
Almaden, Yolanda