RUNX3 plays an important role in mediating the BMP9-induced osteogenic differentiation of mesenchymal stem cells

Abstract

Although bone morphogenetic protein 9 (BMP9) is highly capable of promoting the osteogenic differentiation of mesenchymal stem cells (MSCs) both in vitro and in vivo, the molecular mechanisms involved remain to be fully elucidated. Runt-related transcription factor (RUNX)3 is an essential regulator of osteoblast/chondrocyte maturation. However, the exact role of RUNX3 in BMP9 osteoinductive activity is unknown. In this study, we sought to investigate the functional role of RUNX3 in the BMP9-induced osteogenic differentiation of MSCs. We found that BMP9 upregulated the endogenous expression of RUNX3 in MSCs. The overexpression or/and knockdown of RUNX3 both increased the levels of alkaline phosphatase (ALP) a marker of BMP9-induced early osteogenic differentiation. Nevertheless, matrix mineralization, a marker of BMP9-induced late osteogenic differentiation was enhanced by the overexpression of RUNX3, whereas it was inhibited by the knockdown of RUNX3. The BMP9-induced expression of osteogenic pivotal transcription factors [inhibitor of differentiation (Id)3, distal-less homeobox 5 (DLX5) and RUNX2)] was further increased by the overexpression of RUNX3; however, it was reduced by the knockdown of RUNX3. However, the expression levels of Id1 and Id2 were both enhanced by the overexpression or/and knockdown of RUNX3. The BMP9-induced phosphorylation of Smad1/5/8 was increased with the overexpression of RUNX3, and yet was decreased with the knockdown of RUNX3. Collectively, our findings suggest that RUNX3 is an essential modulator of the BMP9-induced osteoblast lineage differentiation of MSCs.

The roles of RUNX3 in cervical cancer cells in�vitro

“…RUNX3 is located on chromosome 1p36.1 and contains a p1 promoter and p2 promoter (6). Alkaline phosphatase (ALP), a marker of BMP9-induced late osteogenic differentiation was enhanced by the overexpression of RUNX3, whereas it was inhibited by the knockdown of RUNX3 (7). It was first reported to be a tumor suppressor gene in gastric epithelial cells (8), and it was also reported to absent or mutated in a variety of cancers for hemizygous deletions (9), protein mislocalization, epigenetic alterations (10), and histone modifications (11).…”

FAK mediates BMP9-induced osteogenic differentiation via Wnt and MAPK signaling pathway in synovial mesenchymal stem cells

“…The function of FAK in osteogenic process of MSCs needs further investigation. BMP9, known as growth differentiation factor 2 (GDF-2), is the protein that exhibits a variety of biological functions and has been widely concerned due to its induction of osteogenic differentiation [12,13]. However, the potential mechanisms of BMP9 used for bone regeneration still remain unclear.…”

“…Osteogenesis of MSCs requires orchestrated regulation of cellular signal transduction processes including BMP, Wnt and MAPK [15,16]. Smad1/ 5/8-dependent signaling transduction can be elicited via the combination BMPs and BMP receptor type I (BMPRI) or BMP receptor type II (BMPRII), which ultimately leads to the expression of bone markers such as ALP, Runx2, Dlx5, OCN and Osx [12,17]. Conversely, loss of BMP/Smad signaling pathways often leads to bone-related diseases, such as osteoporosis [18].…”

Changed cellular functions and aberrantly expressed miRNAs and circRNAs in bone marrow stem�cells in osteonecrosis of the femoral head

“…miR-214-3p overexpression suppresses cell proliferation in gastric cancer by targeting runt-related transcription factor (RUNX3). In mesen-chymal stem cell (MSCs), RUNX3 plays an important role in mediating the bone morphogenic protein (BMP)9-induced osteogenic differentiation (38,39). miR-144-3p inhibits the proliferation and osteogenic differentiation in MSC lines C3H10T1/2, by directly targeting mothers against decapentaplegic homolog 4 (40).…”