Estradiol (E2) is a major determinant of gender-based differences in the development of hepatic fibrosis. MicroRNAs (miRNAs) are endogenous 19-25 nucleotide, noncoding, single-stranded RNAs that regulate gene expression by blocking the translation or decreasing the stability of mRNAs and play an important role in liver fibrosis. The mechanisms underlying the regulation of miRNAs by E2 remain largely unknown. In this study, miR-19b levels were higher and were associated with lower GRB2 mRNA and protein levels in female rats more than in male rats. We also showed that miR-19b levels were down-regulated, were associated with the up-regulation of GRB2 mRNA and protein levels in PS (porcine serum-induced hepatic fibrosis) versus NS (normal control) groups and were up-regulated when associated with the down-regulation of GRB2 mRNA and protein levels in PS + E2 versus PS and in aHSC + E2 (estradiol treated aHSC) versus aHSC groups. MiR-19b expression inhibited cell proliferation in aHSCs, and also down-regulated GRB2 protein expression. The overexpression of miR-19b inhibited cell growth and suppressed COL1A1 protein levels by decreasing the levels of GRB2. However, the forced expression of GRB2 partly rescued the effect of miR-19b in the cells, attenuated cell proliferation, and suppressed the GRB2 protein level by up-regulating the levels of GRB2. Taken together, these findings will shed light on the role of miR-19b in regulating aHSC proliferation via the miR-19b/GRB2 axis. This newly identified miR-19b/GRB2 interaction provided novel insights into the suppressive effect of E2 on HSC proliferation and might facilitate the development of therapies targeting hepatic fibrosis.

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LncRNAs and microRNAs play critical roles in osteoblast differentiation and bone formation. However, their exact roles in osteoblasts under fluid shear stress (FSS) and the possible mechanisms remain unclear. The aim of this study was to explore whether and how miR‐34a regulates osteoblast proliferation and apoptosis under FSS. In this study, FSS down‐regulated miR‐34a levels of MC3T3‐E1 cells. MiR‐34a up‐regulation attenuated FSS‐induced promotion of proliferation and suppression of apoptosis. Luciferase reporter assay revealed that miR‐34a directly targeted FGFR1. Moreover, miR‐34a regulated osteoblast proliferation and apoptosis via FGFR1. Further, we validated that lncRNA TUG1 acted as a competing endogenous RNA (ceRNA) to interact with miR‐34a and up‐regulate FGFR1 protein expression. Furthermore, lncRNA TUG1 could promote proliferation and inhibit apoptosis. Taken together, our study revealed the key role of the lncRNA TUG1/miR‐34a/FGFR1 axis in FSS‐regulated osteoblast proliferation and apoptosis and may provide potential therapeutic targets for osteoporosis.

Piezo1, a mechanosensitive ion channel, participates in a variety of biological processes in maintaining bone homeostasis. As the most abundant cells in bones of the mammals, osteocytes play an essential role in bone formation, remodeling, and bone mass maintenance. Here, by exposing MLO-Y4 osteocytes to the fluid shear stress (FSS) microenvironment, we explored the effect of Piezo1-mediated FSS on the expression of the molecules critical to the process of bone formation and resorption, Receptor Activator of Nuclear Factor-Kappa-B Ligand (RANKL) and Osteoprotegerin (OPG). It was found that 9 dyne/cm 2 loading for 30 minutes showed an upregulation trend on Piezo1 when MLO-Y4 osteocytes were exposed to an FSS microenvironment. FSS promotes the expression of OPG and inhibits the expression of RANKL. The blocker of Piezo1, GsMTx4, downregulates the effect of FSS on the expression of these two molecules. In addition, NOTCH3 was involved in this process. Thus, the results demonstrated that Piezo1-mediated FSS promotes the expression of OPG and inhibits the expression of RANKL via NOTCH3 in MLO-Y4 osteocytes.

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