MiR-539-3p impairs osteogenesis by suppressing Wnt interaction with LRP-6 co-receptor and subsequent inhibition of Akap-3 signaling pathway

Abstract

X-linked hypophosphatemia (XLH), an inheritable form of rickets is caused due to mutation in Phex gene. Several factors are linked to the disease’s aetiology, including non-coding RNA molecules (miRNAs), which are key post-transcriptional regulators of gene expression and play a significant role in osteoblast functions. MicroRNAs sequence analysis showed differentially regulated miRNAs in phex silenced osteoblast cells. In this article, we report miR-539-3p, an unidentified novel miRNA, in the functional regulation of osteoblast. MiR-539-3p overexpression impaired osteoblast differentiation. Target prediction algorithm and experimental confirmation by luciferase 3’ UTR reporter assay identified LRP-6 as a direct target of miR-539-3p. Over expression of miR-539-3p in osteoblasts down regulated Wnt/beta catenin signaling components and deteriorated trabecular microarchitecture leading to decreased bone formation in ovariectomized (Ovx) mice. Additionally, biochemical bone resorption markers like CTx and Trap-5b were elevated in serum samples of mimic treated group, while, reverse effect was observed in anti-miR treated animals along with increased bone formation marker P1NP. Moreover, transcriptome analysis with miR-539-3p identified a novel uncharacterized Akap-3 gene in osteoblast cells, knock down of which resulted in downregulation of osteoblast differentiation markers at both transcriptional and translational level. Overall, our study for the first time reported the role of miR-539-3p in osteoblast functions and its downstream Akap-3 signalling in regulation of osteoblastogenesis.

Feeding a low-carbohydrate and high-protein diet diminishes working memory in healthy mice: possible involvement of miR-539-3p/Lrp6/Igf1raxis in the hippocampus

“…MiR-539-3p targets not only Igf1r and Lrp6 genes but also Akap3, Rnf2, and Adamts5 genes, as reported in previous studies [33,39,40]. Our current study revealed that feeding the LC-HP diet downregulated hippocampal mRNA levels of Akap3, while no significant changes were observed in Rnf2 or Adamts5 mRNAs (Fig.…”

“…Of particular interest was miR-539-3p, as it is also predicted to target pathways related to IGF-1R. Previous research has demonstrated that miR-539-3p downregulates Lrp6 mRNA levels [33], and LRP6, in turn, regulates expressions and activation of IGF-1R [34,35]. LRP6 plays a critical role in Wnt/β-catenin signal transduction [36–38].…”

“…downregulates Lrp6 mRNA levels [33], and LRP6, in turn, regulates expressions and activation of IGF-1R [34,35]. LRP6 plays a critical role in Wnt/β-catenin signal transduction [36][37][38].…”

Prevalence and plasma exosome-derive microRNA diagnostic biomarker screening of adolescent idiopathic scoliosis in Yunnan Province, China

“…Pepe et al ( 55 ) discovered that extracellular vesicle-derived miR-1246 is linked to osteoclast differentiation. Tripathi et al ( 62 ) found that miR-539 is related to the regulation of osteoblastogenesis. Based on this evidence, it is inferred that the aberrant expression of hsa-miRNA-27a-5p, hsa-miRNA-539-5p, and hsa-miRNA-1246 in AIS patients may be associated with the progression of AIS.…”

lncRNA CCAT2 Protects Against Cardiomyocyte Injury After Myocardial Ischemia/Reperfusion by Regulating BMI1 Expression

“…The luciferase reporter gene assay indicated that miR-539-3p could bind to CCAT2 and BMI1. Previous studies have indicated that miR-539-3p can regulate chondrogenic differentiation, 40) osteoblast functions, 41) and tumor progression. 42) Additionally, miR-539-3p was upregulated after I/R injury, and its overexpression exerted detrimental effects on myocardial I/R injury.…”