MicroRNA-181a/b-1 over-expression enhances osteogenesis by modulating PTEN/PI3K/AKT signaling and mitochondrial metabolism

Abstract

MicroRNAs are small non-coding RNAs that play important roles in many cellular processes including proliferation, metabolism and differentiation. They function by binding to specific regions within the 3'UTR of target mRNAs resulting in suppression of protein synthesis and modulation of potentially many cellular pathways. We previously showed that miRNA expression levels differed between cells from distinct regions of developing human embryonic long bones. Specifically, we found that miR-181a-1 was significantly more highly expressed in hypertrophic chondrocytes compared to proliferating differentiated or progenitor chondrocytes, suggesting a potential role in regulating chondrocyte hypertrophy and/or endochondral bone formation. The goal of this study was to determine how miR-181a-1 together with its clustered miRNA, miR-181b-1, regulates osteogenesis. We show that over-expression of the miR-181a/b-1 cluster enhanced osteogenesis and that cellular pathways associated with protein synthesis and mitochondrial metabolism were significantly up-regulated. Metabolic assays revealed that the oxygen consumption rate and ATP-linked respiration were increased by miR-181a/b-1. To further decipher a potential mechanism causing these metabolic changes, we showed that PTEN (phosphatase and tensin homolog) levels were suppressed following miR-181a/b-1 overexpression, and that PI3K/AKT signaling was subsequently increased. Over-expression of PTEN

miR‐181a regulates p62/SQSTM1, parkin, and protein DJ‐1 promoting mitochondrial dynamics in skeletal muscle aging

“…miR‐181a‐mediated regulation of components of autophagy has previously been reported in aging, cancer cell lines, and nervous system (Cheng et al, 2016; Indrieri et al, 2019; Rippo et al, 2014; Soriano‐Arroquia, House, Tregilgas, Canty‐Laird, & Goljanek‐Whysall, 2016; Tekirdag, Korkmaz, Ozturk, Agami, & Gozuacik, 2013). Recently, overexpression of miR‐181a/b‐1 in chondrocytes resulted in improvements in mitochondrial metabolism (Zheng, Liu, Tycksen, Nunley, & McAlinden, 2019). Our results indicate miR‐181a regulates autophagy/mitophagy and effector proteins, providing a mechanism of fine‐tuning mitochondrial dynamics through parallel regulatory pathways.…”

Destroy to Rebuild: The Connection Between Bone Tissue Remodeling and Matrix Metalloproteinases

“…Moreover, the activation of calcineurin involves the activation of phospholipase-Cγ and Tec kinases (Mocsai et al, 2004;Faccio et al, 2005;Wada et al, 2005). In general, most signaling pathways (MAPKs, NF-κB, AP-1, Ca(II), Src/PI3K/AKt) which are activated in the osteoclast converge to induce the activity of NFATc1 (Gori et al, 2000;Ishida et al, 2002;Takayanagi et al, 2002;Matsuo et al, 2004;Paiva and Granjeiro, 2017;Plotkin and Bruzzaniti, 2019;Zheng et al, 2019). Upon translocation to the nucleus, NFATc1 acts together with c-fos to promote the expression of key osteoclast genes.…”

LncRNA NKILA integrates RXFP1/AKT and NF‐κB signalling to regulate osteogenesis of mesenchymal stem cells

“…NKILA is found to positively regulate the expression of RXFP1. Furthermore, we demonstrate that NKILA could dramatically enhance the activity of AKT, another crucial positive regulator of osteogenic differentiation, 21,33,34 and a downstream regulator of Relaxin/RXFP1 pathway.…”