Hedgehog signaling is involved in the BMP9-induced osteogenic differentiation of mesenchymal stem cells

Abstract

Mesenchymal stem cells (MSCs) are multipotent progenitor cells that can undergo self-renewal and differentiate into multiple lineages. Osteogenic differentiation from MSCs is a well-orchestrated process and regulated by multiple signaling pathways. We previously demonstrated that BMP9 is one of the most potent osteogenic factors. However, molecular mechanism through which BMP9 governs osteoblastic differentiation remains to be fully understood. Increasing evidence indicates noncoding RNAs (ncRNAs) may play important regulatory roles in many physiological and/or pathologic processes. In this study, we investigate the role of lncRNA H19 in BMP9-regulated osteogenic differentiation of MSCs. We demonstrated that H19 was sharply upregulated at the early stage of BMP9 stimulation of MSCs, followed by a rapid decease and gradual return to basal level. This process was correlated with BMP9-induced expression of osteogenic markers. Interestingly, either constitutive H19 www.impactjournals.com/oncotarget/ Oncotarget 53582 www.impactjournals.com/oncotarget expression or silencing H19 expression in MSCs significantly impaired BMP9-induced osteogenic differentiation in vitro and in vivo, which was effectively rescued by the activation of Notch signaling. Either constitutive H19 expression or silencing H19 expression led to the increased expression of a group of miRNAs that are predicted to target Notch ligands and receptors. Thus, these results indicate that lncRNA H19 functions as an important mediator of BMP9 signaling by modulating Notch signaling-targeting miRNAs. Our findings suggest that the well-coordinated biphasic expression of lncRNA H19 may be essential in BMP9-induced osteogenic differentiation of MSCs, and that dysregulated H19 expression may impair normal osteogenesis, leading to pathogenic processes, such as bone tumor development.

Notch signaling pathway promotes osteogenic differentiation of mesenchymal stem cells by enhancing BMP9/Smad signaling

“…It has been demonstrated in our previous study that runt-related transcription factor 2 (Runx2), inhibitor of differentiation (Id)1, 2 and 3 are targets of BMP9, and are critical to BMP9-induced osteogenic differentiation in MSCs (40). Type I collagen (Colla1) is the special collagen secreted by osteoblast cells.…”

“…Cox2 is critical for BMP9 to induce osteogenic differentiation in MSCs (39). Hedgehog signaling is involved and plays a regulatory role in the osteogenic differentiation of MSCs induced by BMP9 (40). Yet, little is known concerning the effect of Notch signaling on BMP9-induced osteogenic differentiation.…”

“…Semi-quantitative RT-PCR was performed as described previously (40,41). The cDNA products were further diluted 5- to 10-fold and used in the successive experiments.…”

Effects of exogenous nerve growth factor on the expression of BMP-9 and VEGF in the healing of rabbit mandible fracture with local nerve injury

“…These bone growth factors include bone morphogenetic protein (BMP), vascular endothelial growth factor (VEGF), broblast growth factor (FGF), transforming growth factor-β (TGF-β) and so on. Among them, BMP-9 and VEGF are responsible for osteogenesis and angiogenesis, respectively [34][35][36][37]. In this paper, a large number of osteoblasts and some vascular endothelial cells were found around the trabecular bone in NGF group at 2th weeks after the operation (Fig.…”

Actin Polymerization State Regulates Osteogenic Differentiation in Human Adipose-derived Stem Cells

“…Osteogenic differentiation of hASCs is a complex process in which multiple genes, proteins, and signaling pathways interact with each other [39][40][41]. The reorganization of the actin cytoskeleton plays an essential role during stem cell differentiation.…”