MicroRNA-133a Regulates the Viability and Differentiation Fate of Bone Marrow Mesenchymal Stem Cells via MAPK/ERK Signaling Pathway by Targeting FGFR1

Abstract

Dysfunction of bone marrow mesenchymal stem cells (BMSCs) is recognized critical in bone deteriorations of osteoporosis. However, the specific mechanisms that determine the fate of BMSCs remain elusive. MicroRNA-133a (miR-133a), a highly conserved microRNA, was investigated under both in vitro and in vivo conditions. In the in vitro study, cell proliferation, cell apoptosis, and osteoblast/adipocyte differentiation of BMSCs as a result of overexpression or knockdown of miR-133a was investigated. In the in vivo study, the ovariectomy (OVX) model was applied on mice, with further treatment of the models with BMSC-specific miR-133a antagomir through femur intramedullary injection. Microcomputed tomography scanning and histological analysis of the proximal and middle femur were performed to evaluate the morphological changes. The results revealed that overexpression of miR-133a suppressed cell proliferation, cell viability, and osteoblast differentiation of BMSCs, but increased adipocyte differentiation. We also found that FGFR1, an important upstream regulator of mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signal pathway, was a major target of miR-133a. We also recorded that BMSC-specific knockdown of miR-133a attenuates bone loss in OVX mice. Our study suggested that miR-133a played an important role in maintaining the viability and balance between osteoblast and adipocyte differentiation of BMSCs through the MAPK/ERK signaling pathway by targeting FGFR1.

Human umbilical cord-derived mesenchymal stem cells not only ameliorate blood glucose but also protect vascular endothelium from diabetic damage through a paracrine mechanism mediated by MAPK/ERK signaling

“…To date, a series of paracrine molecules excreted by MSCs have been discovered, including cytokines, growth factors, exosomes, and non-coding RNAs. Many of them are involved in the regulation of MAPK/ERK signaling pathway (Table 3) [45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62]. Of these, ERBB4, Spred1, miR-125b, HOTAIRM1-1, and miR-133a are negative regulators, while HIF-2α, IGF-1, TGF-β3, bFGF, VEGF, BDNF, METTL1, FGF8, IGF-1, SCGF-beta, HGF, MCP-1, miR-126, SMSCs-126-Exos, ApoE, IL-8, and IL-6 are positive regulators.…”

Novel Targets and Therapeutic Strategies to Protect Against Hepatic Ischemia Reperfusion Injury

“…In this part, we review the latest research concerning the role and mechanism of several important miRNAs in liver IRI. miR-122 is the most abundant miRNA in the liver, accounting for almost 70% of the total amount of liver miRNA (18). In 2012, Andersson et al designed an ischemic porcine cardiogenic shock model and found that circulating miR-122 levels were increased nearly 460,000-fold after cardiogenic shock, whereas classic markers of hepatocellular necrosis were only modestly elevated nearly 3-fold, and miR-122 levels significantly decreased after therapeutic hypothermia (102).…”

“…miRNAs are a type of non-coding RNA, usually comprised of 19-24 nucleotides, and are the most important gene-regulatory factors at the post-transcriptional level. Previous studies have reported that miRNAs are closely associated with a variety of diseases or dysfunction ( 18 ). Chinese scholars Ng et al ( 19 ) reported that miRNAs may also be involved in liver IRI, as the expression of several circulating miRNAs, including miR-1246, miR-148a, and miR-1290, was upregulated after liver transplantation.…”

“…Very recently, it was reported that the activation of peroxisome proliferator-activated receptor γ (PPARγ), a member of a superfamily of nuclear transcription factors activated by agonists, can attenuate IRI in the liver ( 15 , 16 ), and FAM3A has been confirmed to mediate the protective effect of PPARγ in hepatic IRI ( 17 ). In addition, non-coding RNAs, like LncRNAs and miRNAs, have also been reported to play a pivotal role in the process of liver IRI ( 18 , 19 ).…”

Morinda officinalis polysaccharide regulates rat bone mesenchymal stem cell osteogenic–adipogenic differentiation in osteoporosis by upregulating miR‐21 and activating the PI3K/AKT pathway

“…3 Dysfunction of BMSCs is identified as essential in bone deteriorations in OP. 4 The differentiation of BMSCs to adipocytes rather than osteoblasts leads to the enhancement of adipogenic differentiation (AD) and the decrease of osteogenic differentiation (OD), which is closely related to the occurrence of OP. 5 Therefore, it is of vital importance to study the regulatory mechanism of therapeutic drugs in OP in terms of the OD and AD of BMSCs, clarify the pathogenesis of OP, and find new gene therapy targets.…”