MiR-361-3p/Nfat5 Signaling Axis Controls Cementoblast Differentiation

Abstract

The development of periodontal tissue is a complex process, including cementoblast proliferation and differentiation. Emerging reports suggest that microRNAs (miRNAs) play crucial roles in gene regulatory networks governing numerous biological processes. However, how miRNAs modulate cementoblast proliferation and differentiation remains largely unknown. In a previous study, we performed miRNA microarray profiling to fully reveal the expression patterns of miRNAs involved in cementoblast differentiation. We focused on miR-361-3p, which decreased during cementoblast differentiation. Overexpression of miR-361-3p resulted in decreased cementoblast differentiation, whereas the functional inhibition of miR-361-3p yielded the opposite effect. The bioinformatics approach identified nuclear factor of activated T-cell 5 ( Nfat5) as a potential target of miR-361-3p, which was further verified by dual luciferase assay. Meanwhile, the expression pattern of Nfat5 was verified both in vitro and in vivo. Furthermore, knockdown of Nfat5 mimicked the inhibitory effect of overexpressing miR-361-3p in cementoblasts. Moreover, multiple signaling pathways, including the Erk1/2, JNK, p38, PI3K-Akt, and NF-κB pathways, were notably activated, and the Wnt/ß-catenin pathway was blocked by downregulation of Nfat5 or forced expression of miR-361-3p in cementoblast differentiation. Finally, the complementary approach demonstrated that miR-361-3p regulated cementoblast differentiation via or partially via Erk1/2 and PI3K-Akt. Overall, our study elucidated that the JNK, p38, NF-κB, and Wnt/ß-catenin pathways act as balancing players in the miR-361-3p/ Nfat5 signaling axis during cementoblast differentiation.

Identification of regulatory mRNA and microRNA for differentiation into cementoblasts and periodontal ligament cells

“…Therefore, these miRNAs can work in concert and efficiently during cementoblast commitment by interacting with each other. Some groups have reported the role of microRNAs in cementogenesis [50][51][52] ; however, in this study, we did not detect the same mRNAs and microRNAs as those detected in previous reports. Taking into consideration that double overexpression of miR-383 and miR-628-5p weakened the enhancement of CEMP1…”

“…Therefore, these miRNAs can work in concert and efficiently during cementoblast commitment by interacting with each other. Some groups have reported the role of microRNAs in cementogenesis 50‐52 ; however, in this study, we did not detect the same mRNAs and microRNAs as those detected in previous reports. Taking into consideration that double overexpression of miR‐383 and miR‐628‐5p weakened the enhancement of CEMP1 and OPN mRNA expression (Figure 2), cementogenesis of MSCs likely regulates some factors, for example, Nfat5, DKK1, miR‐361‐3p, miR3064‐3p, or miR‐155‐3p, and the underlying mechanisms must be elucidated.…”

LncRNA lnc‐ISG20 promotes renal fibrosis in diabetic nephropathy by inducing AKT phosphorylation through miR‐486‐5p/NFAT5

“…NFAT5 has been previously demonstrated to interact with multiple signalling pathways. 39 Considering that the AKT pathway is activated in the DN rat model, which shares a relationship with renal fibrosis, 40 the activation of AKT pathway could be a possible target to affect the renal fibrosis in DN. Therefore, we tested whether NFAT5 would affect the activation of AKT.…”

NFAT5-Mediated Signalling Pathways in Viral Infection and Cardiovascular Dysfunction

“…Additionally, several miRNA/NFAT pathways have been shown to be involved in cellular differentiation and macrophage polarization. One of the key regulators of cementoblast differentiation is the miR-361-3p/NFAT5 axis, which is associated with many important signalling pathways including ERK1/2, JNK, p38, PI3K/Akt, NF-κB and Wnt/β-catenin [ 54 ]. Furthermore, miR-223 is required for PPARγ-dependent macrophage alternative activation.…”