Maresin1 Suppresses High-Glucose-Induced Ferroptosis in Osteoblasts via NRF2 Activation in Type 2 Diabetic Osteoporosis

Zhanwei Zhang; Chonghao Ji; Ya-Nan Wang; Shiyue Liu; Maoshan Wang; Xin Xu; Dongjiao Zhang

doi:10.3390/cells11162560

Maresin1 Suppresses High-Glucose-Induced Ferroptosis in Osteoblasts via NRF2 Activation in Type 2 Diabetic Osteoporosis

Cells. 2022 Aug 17;11(16):2560. doi: 10.3390/cells11162560.

Authors

Zhanwei Zhang¹, Chonghao Ji¹, Ya-Nan Wang¹, Shiyue Liu², Maoshan Wang¹, Xin Xu¹, Dongjiao Zhang¹

Affiliations

¹ Department of Implantology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, No. 44-1 Wenhua Road West, Jinan 250012, China.
² Department of Periodontology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, No. 44-1 Wenhua Road West, Jinan 250012, China.

Abstract

Maresin1 (MaR1) is an endogenous pro-resolving lipid mediator produced from polyunsaturated fatty acids and is believed to have antioxidant and anti-inflammatory properties. The objective of this study was to estimate MaR1's impact on type 2 diabetic osteoporosis (T2DOP) and its pharmacological mode of action. An in vitro high-glucose model of the osteoblast cell line MC3T3-E1 was constructed and stimulated with MaR1. Type 2 diabetic rats were used to establish in vivo models of calvarial defects and were treated in situ with MaR1. The results revealed that, aside from preventing mortality and promoting the osteogenic capacity of MC3T3-E1 cells, MaR1 increased nuclear factor erythroid-2 related factor 2 (NRF2) signaling as well as the activity of glutathione peroxidase 4 (GPX4) and cystine-glutamate antiporter (SLC7A11) and caused the restraint of ferroptosis under hyperglycemic stimulation. However, the therapeutic impact of MaR1 was significantly diminished due to NRF2-siRNA interference and the ferroptosis activator Erastin. Meanwhile, these results were validated through in vivo experiments. These findings imply that MaR1 activated the NRF2 pathway in vivo and in vitro to alleviate high-glucose-induced ferroptosis greatly. More crucially, MaR1 might effectively reduce the risk of T2DOP.

Keywords: NRF2; diabetic osteoporosis; ferroptosis; glutathione peroxidase 4; maresin1.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Diabetes Mellitus, Experimental*
Diabetes Mellitus, Type 2* / complications
Docosahexaenoic Acids / pharmacology*
Ferroptosis*
Glucose / pharmacology
NF-E2-Related Factor 2 / metabolism
Osteoblasts / metabolism
Osteoporosis*
Rats

Substances

7,14-dihydroxydocosa-4,8,10,12,16,19-hexaenoic acid
NF-E2-Related Factor 2
Docosahexaenoic Acids
Glucose

Grants and funding

This research was funded by the National Natural Science Foundation of China, grant no. 82071148; the Natural Science Foundation of Shandong Province, grant no. ZR2021MH092; and the Natural Science Foundation of Jiangsu Province, grant no. BK20210111. The APC was funded by the National Natural Science Foundation of China, grant no. 82071148.