Work

Exploring the role of metformin in high fluoride ingestion-induced bone lesions

Year: 2025

Type: article

Abstract: This study was to investigate the potential mechanisms of metformin administration against skeletal fluorosis by mitigating bone turnover. Rats were treated with fluoride via intragastric gavage to develop a model of skeletal fluorosis, and half of them were concurrently treated with metformin for 12 weeks. The cells involved in the process of bone turnover, including osteoclasts, osteoblast, and osteocyte were exposed to varying concentrations of fluoride with or without metformin. Results showed that excessive fluoride treatment increased levels of bone turnover markers in the serum and the expression of bone turnover-related factors in the femur. Additionally, fluoride treatment damaged the trabecular microstructure and mechanical function in long bone. Concurrent treatment of metformin reduced the serum levels of bone turnover markers and protein expression of bone turnover-related factors in the femurs of fluorotic rats. Furthermore, metformin cotreatment restored the trabecular microstructure of and mechanical function of the long bones of fluorotic rats. In vitro studies demonstrated that low-dose fluoride stimulated osteoclastic viability and upregulated osteoclastic differentiation proteins, but metformin inhibited the stimulatory effect of fluoride on them. Though fluoride exposure increased the apoptosis rate of osteoclasts and osteoblasts, and metformin aggravated fluoride-induced osteoclastic apoptosis but alleviated osteoblastic apoptosis. Additional, metformin stimulated SOST expression and inhibited RANKL expression in osteocytes exposed to fluoride. This is consistent with the KEGG enriched pathway in metformin-treated osteocytes, such as the osteoclast differentiation and Wnt signaling pathways. These results suggested that metformin counteracted high bone turnover that occurred in skeletal fluorosis by inhibiting osteoclastogenesis and regulating osteocytes to delay osteogenesis. • Metformin inhibited increase of bone turnover markers in skeletal fluorosis rats. • Metformin mitigated fluoride-induced bone microstructure and mechanical function damages. • Metformin inhibited fluoride-stimulating osteoclastic activity instead of osteoblast. • Metformin enriched Wnt and Osteoclastic signaling pathways by RNA-seq of osteocytes. • Metformin upregulated expression of SOST, an inhibitor of bone formation.

Source: Toxicology and Applied Pharmacology

DOI: 10.1016/j.taap.2025.117653

Authors: Wenshu Xu, Ningning Jiang, Zhongyuan Zhang, Hui Xu

Institution: Jilin University

Language: English

Topic: Fluoride Effects and Removal

Subfield: Water Science and Technology

Field: Environmental Science

Domain: Physical Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $4,200