Abstract
Fluorine is widely dispersed in nature and has multiple physiological functions. Although it is usually regarded as an essential trace element for humans, this view is not held universally. Moreover, chronic fluorosis, mainly characterized by skeletal fluorosis, can be induced by long-term excessive fluoride consumption. High concentrations of fluoride in the environment and drinking water are major causes, and patients with skeletal fluorosis mainly present with symptoms of osteosclerosis, osteochondrosis, osteoporosis, and degenerative changes in joint cartilage. Etiologies for skeletal fluorosis have been established, but the specific pathogenesis is inconclusive. Currently, active osteogenesis and accelerated bone turnover are considered critical processes in the progression of skeletal fluorosis. In recent years, researchers have conducted extensive studies in fields of signaling pathways (Wnt/β-catenin, Notch, PI3K/Akt/mTOR, Hedgehog, parathyroid hormone, and insulin signaling pathways), stress pathways (oxidative stress and endoplasmic reticulum stress pathways), epigenetics (DNA methylation and non-coding RNAs), and their inter-regulation involved in the pathogenesis of skeletal fluorosis. In this review, we summarised and analyzed relevant findings to provide a basis for comprehensive understandings of the pathogenesis of skeletal fluorosis and hopefully propose more effective prevention and therapeutic strategies.
Highlights
Fluorine is one of the most common halogens, which usually exists in the environment as compounds
A study has shown that fluoride exposure activates the protein kinase-like ER kinase (PERK) signaling pathway, leading to activation of activating transcription factor 4 (ATF4) and nuclear factor erythroid 2-related factor 2 (Nrf2) and up-regulating the expression of genes related to bone turnover in osteoblasts [89]
To further clarify the role of the PERK signaling pathway, changes in osteogenic and osteolytic gene expression were studied in osteoblastic cell lines before and after PERK gene interference, and the results showed that fluoride stimulated the protein expression of PERK, Nrf2, osteoprotegerin (OPG), and Runx2 in PERK siRNA-transfected cells to a certain extent [90]
Summary
Fluorine is one of the most common halogens, which usually exists in the environment as compounds. A recent study found that fluoride can induce abnormal activation of the Wnt/β-catenin signaling pathway, causing the increased formation of cancerous bone in mice and protein expression of Wnt3a and phospho-Gsk-3β, as well as its downstream target gene Runt-related transcription factor 2 (Runx). An animal experiment found that excessive fluoride exposure decreased the protein as well as mRNA expression levels of Notch‐3 and Jagged‐1 in rats, especially in osteoblasts [32], suggesting that fluoride can inhibit the Notch signaling pathway, promoting osteoblasts proliferation and differentiation, disturbed dynamic homeostasis of bone tissue, and the pathological manifestation of o4s‐of 17 teosclerosis. Skeletal fluorosis is characterized by a disrupted dynamic balance between bone resorption and formation and is intimately linked to regulating PI3K/Akt/mTOR signaling pathway, with a critical role in osteoblast proliferation and differentiation as well as chondrocyte autophagy. Understanding more about the changes of PI3K/Akt/mTOR signaling pathway and related signaling molecules in skeletal fluorosis, as well as its interaction with other signaling pathways, will promote a profound understanding of the pathogenesis of endemic fluorosis and provide a basis for the prevention and treatment of skeletal fluorosis
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