Abstract
Osteogenic differentiation in human bone marrow-derived mesenchymal stem cells (hBMSCs) is regulated by various factors, including bone morphogenetic proteins (BMPs), Notch, growth hormones and mitogen-activated protein kinases (MAPKs). Tribbles homolog 3 (TRIB3), a pseudokinase, plays an important role in cancer cells and adipocytes. However, TRIB3 function in osteogenic differentiation is unknown, although it is involved in regulating signaling pathways associated with osteogenic differentiation. Here, we found that TRIB3 was highly expressed during osteogenic differentiation in hBMSCs. Inhibition of focal adhesion kinase (FAK) or phosphatidylinositol 3-kinase (PI3K) resulted in a significant decrease in TRIB3 expression, and expression of TRIB3 was restored by increasing insulin-like growth factor-1 (IGF-1) via activating phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling. TRIB3 knock-down enhanced proliferation and decreased osteogenic differentiation at the middle stage of differentiation, and these effects were reversed by inhibiting the activation of extracellular signal-regulated kinase (ERK)-1/2. In conclusion, TRIB3 plays an important role in proliferation and osteogenic differentiation by regulating ERK1/2 activity at the middle stage of differentiation, and expression of TRIB3 is regulated by FAK in a PI3K/AKT-dependent manner.
Highlights
Human bone marrow-derived mesenchymal stem cells have the potential to differentiate into various lineages of mesenchymal tissues, such as bone, cartilage, fat, muscle, and marrow stroma1. human bone marrow-derived mesenchymal stem cells (hBMSCs) have been used as a promising cell source for the regeneration of tissues, including bone, in several clinical trials[2, 3]
Our results showed that Tribbles homolog 3 (TRIB3) was overexpressed in osteogenically induced cells and that TRIB3 expression was regulated by focal adhesion kinase (FAK) activity in a phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT)-dependent manner
These results indicate that TRIB3 is expressed throughout osteogenic differentiation and its expression level increases with the induction time, suggesting an important role for TRIB3 in osteogenic differentiation in hBMSCs
Summary
Human bone marrow-derived mesenchymal stem cells (hBMSCs) have the potential to differentiate into various lineages of mesenchymal tissues, such as bone, cartilage, fat, muscle, and marrow stroma1. hBMSCs have been used as a promising cell source for the regeneration of tissues, including bone, in several clinical trials[2, 3]. TRIB3 is known as a master regulator of Notch via the MAPK-ERK and TGF-β pathways and is required for the growth of basal-like breast cancer[25]. These signaling pathways are associated with the regulation of osteogenic differentiation, but the function of TRIB3 in osteogenic differentiation is unknown. We investigated the role of TRIB3 in osteogenic differentiation in hBMSCs. Our results showed that TRIB3 was overexpressed in osteogenically induced cells and that TRIB3 expression was regulated by focal adhesion kinase (FAK) activity in a phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT)-dependent manner. TRIB3 inhibited cell proliferation and promoted osteogenic differentiation in hBMSCs by inhibiting the activity of extracellular signal-regulated kinase (ERK)-1/2 at the middle stage of osteogenesis
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