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

Abstract

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.

Endoplasmic reticulum chaperone GRP78 participates in fluoride‐induced autophagy in LS8 cells by regulating the IRE1‐TRAF2‐JNK pathway

“…High doses of fluoride induce stress in various dental cells, [1][2][3][4] including dental tissue cells such as ameloblasts, 5,6 odontoblasts and osteoblasts. 7,8 In ameloblasts, fluoride can induce endoplasmic reticulum (ER) stress, 9 a stress response that inhibits protein synthesis and secretion during enamel formation. As a compensatory defense mechanism against ER stress, the unfolded protein response (UPR) removes unfolded/misfolded proteins and prevents their accumulation.…”

Fluoride in the Central Nervous System and Its Potential Influence on the Development and Invasiveness of Brain Tumours—A Research Hypothesis

“…TGF-β1 is also known to play a mediating role in NaF-induced autophagy in mouse osteoblast cells [ 246 ]. In studies on human osteoblasts, NaF was observed to activate the TGF-β1/Smad2/3/CyclinD1 axis [ 247 ]. Animal studies demonstrated an increase in TGF-β levels in periodontal soft tissues [ 248 ] and an increase in TGF-β expression through an increase in IL-17A expression in testes [ 249 ].…”

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

“…miR-124 and miR-155 are reported to be critical players in fluorosis biology [106]. The recent finding of increased cyclinD1 expression due to miR-486-3p made a significant contribution to understanding the mechanism of skeletal fluorosis [107]. Finding that cyclinD1 is also a direct target of miR-4755-5p, and fluoride exposure suppresses miR-4755-5p and induces cyclinD1 protein in osteoblasts, thus shedding new light upon fluorosis treatment [108].…”