Increased Wnt/β-catenin signaling contributes to autophagy inhibition resulting from a dietary magnesium deficiency in injury-induced osteoarthritis

Abstract

Background 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. Methods 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. Results 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. Conclusions 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.

Integrated Analysis of Transcriptome Changes in Osteoarthritis: Gene Expression, Pathways and Alternative Splicing

“…13 Recent investigation into OA shows articular chondrocyte homeostasis could be disrupted by overweight, aging as well as genetic alterations in tumor growth factor (TGF)-β/Smad, Wnt/β-catenin, and Ihh signaling pathways. [14][15][16][17] The upregulation of catabolic enzymes like matrix metalloproteinases (MMP)-13 and ADAMTS5 in most mouse models of OA suggest that these enzymes may serve as the potential therapeutic targets in the intervention of the progression of the OA. 18 Recently, with the development of high-throughput sequencing technology, more and more studies have attempted to find the possible and potential mechanism of the pathogenesis and progression of OA by performing multi-omics sequencing.…”

“…13 Recent investigation into OA shows articular chondrocyte homeostasis could be disrupted by overweight, aging as well as genetic alterations in tumor growth factor (TGF)-β/Smad, Wnt/β-catenin, and Ihh signaling pathways. 14 -17 The upregulation of catabolic enzymes like matrix metalloproteinases (MMP)-13 and ADAMTS5 in most mouse models of OA suggest that these enzymes may serve as the potential therapeutic targets in the intervention of the progression of the OA. 18…”

Engineered MgO nanoparticles for cartilage-bone synergistic therapy

“…Magnesium (Mg) is an element that is mainly stored in the skeletal system and plays a crucial role in maintaining bone and cartilage health (13)(14)(15)(16). Previous studies have revealed the link between magnesium ion (Mg 2+ ) deficiency and the progression of OA (17,18). Notably, oral and intra-articular Mg 2+ supplementation has shown beneficial effects in OA treatment (19)(20)(21).…”

AMPK/mTOR Pathway Is Involved in Autophagy Induced by Magnesium-Incorporated TiO2 Surface to Promote BMSC Osteogenic Differentiation

“…Autophagy is greatly influenced by magnesium, but the effect is quite complex. Studies have reported that dietary magnesium deficiency reduces the number of autolysosomes and autophagosomes [ 34 ]. Magnesium incorporated in biomaterials triggers autophagy to mediate apoptosis in osteosarcoma cells [ 35 , 36 ].…”