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.

Progress of Signaling Pathways, Stress Pathways and Epigenetics in the Pathogenesis of Skeletal Fluorosis.

Let-7c-5p Regulates CyclinD1 in Fluoride-Mediated Osteoblast Proliferation and Activation.

Fluoride is a persistent environmental pollutant, and its excessive intake contributes to skeletal and dental fluorosis The mechanisms underlying fluoride-induced abnormal osteoblast proliferation and activation, which are related to skeletal fluorosis, have not yet been fully clarified As important epigenetic regulators, microRNAs (miRNAs) participate in bone metabolism On the basis of our previous miRNA-seq results and bioinformatics analysis, this study investigated the role and specific molecular mechanism of miR-486-3p in fluoride-induced osteoblast proliferation and activation via CyclinD1 Herein, in the fluoride-challenged population, we observed that miR-486-3p expression decreased while CyclinD1 and transforming growth factor (TGF)-β1 increased, and miR-486-3p level correlated negatively with the expression of CyclinD1 and TGF-β1 genes Further, we verified that sodium fluoride (NaF) decreases miR-486-3p expression in human osteoblasts and overexpression of miR-486-3p reduces fluoride-induced osteoblast proliferation and activation Meanwhile, we demonstrated that miR-486-3p regulates NaF-induced upregulation of CyclinD1 by directly targeting its 3'-untranslated region (3'-UTR) In addition, we observed that NaF activates the TGF-β1/Smad2/3/CyclinD1 axis and miR-486-3p mediates transcriptional regulation of CyclinD1 by TGF-β1/Smad2/3 signaling pathway via targeting TGF-β1 3'-UTR in vitro This study, thus, contributes significantly in revealing the mechanism of miR-486-3p-mediated CyclinD1 upregulation in skeletal fluorosis and sheds new light on endemic fluorosis treatment

miR-486-3p regulates CyclinD1 and promotes fluoride-induced osteoblast proliferation and activation.

Altered miRNA expression profiling in enamel organ of fluoride affected rat embryos.

Sodium fluoride (NaF) is widely used in clinical dentistry. However, the administration of high or low concentrations of NaF has various functions in different tissues. Understanding the mechanisms of the different effects of NaF will help to optimize its use in clinical applications. Studies of NaF and epithelial cells, osteoblasts, osteoclasts, and periodontal cells have suggested the significant roles of fluoride treatment. In this review, we summarize recent studies on the biphasic functions of NaF that are related to both soft and hard periodontal tissues, multiple diseases, and clinical dentistry.

https://www.mdpi.com/1422-0067/23/2/962/pdf?version=1642327219

Biphasic Functions of Sodium Fluoride (NaF) in Soft and in Hard Periodontal Tissues

Chronic intake of fluoride, existing in the environment, may cause endemic fluorosis, which is characterized by the occurrence of skeletal and dental fluorosis. However, the pathogenesis of fluorosis has not yet been elucidated. Abnormal osteoblast proliferation and activation have a pivotal role in bone turnover disorders which are linked to skeletal fluorosis. MicroRNAs are involved in fundamental cellular processes, including cell proliferation. Based on our previous study, population study and in vitro experiments were designed to understand the effect of miR-122-5p on osteoblast activation in skeletal fluorosis through targeting cyclin-dependent kinase 4 (CDK4). In human populations with coal-burning type fluoride exposure, the results showed that miR-122-5p was downregulated but CDK4 expression was upregulated and miR-122-5p was negatively correlated with CDK4 expression. Furthermore, in human osteoblasts treated with sodium fluoride, we demonstrated that miR-122-5p mediated osteoblast activation of skeletal fluorosis via upregulation of the CDK4 protein. In support of this, dual-luciferase reporter assay showed that miR-122-5p modulated CDK4 protein levels by targeting its 3′-untranslated region. These findings show, for the first time, that miR-122-5p may be involved in the cause and development of skeletal fluorosis by targeting CDK4.

Ting Ouyang

Papers

miR-122-5p Mediates Fluoride-Induced Osteoblast Activation by Targeting CDK4

Let-7c-5p Regulates CyclinD1 in Fluoride-Mediated Osteoblast Proliferation and Activation.

miR-486-3p regulates CyclinD1 and promotes fluoride-induced osteoblast proliferation and activation.