High‐mobility group box‐B1 (HMGB1) mediates the hypoxia‐induced mesenchymal transition of osteoblast cells via activating ERK/JNK signaling

Abstract

High-mobility group box 1 (HMGB1) is a nuclear protein that involves the binding with DNA and influences chromatin regulation and transcription. HMGB1 activates monocytes and neutrophils, which are involved in inflammation during wounding. In this study, we investigated the promotion of HMGB1 under hypoxia and determined the regulatory role of HMGB1 on the fibrosis of mouse osteoblast-like MC3T3-E1 cells or of human osteoblast MG-63 cells. Results demonstrated that HMGB1 expression was significantly upregulated in MC3T3-E1 or MG-63 cells under hypoxia. We also found that treatment with 10 and 100 ng/mL of HMGB1 significantly promoted the fibrosis-associated markers such as Collagen I, α-SMA, whereas downregulated the E-cadherin, indicating the differentiation of MC3T3-E1 or MG-63 cells into fibroblast cells. Further investigation indicated that the HMGB1 treatment markedly activated the mitogen-activated protein kinases (MAPKs), including extracellular signal-related kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (p38) phosphorylation, as well as nuclear factor (NF)-κB nuclear translocation. On the other side, using specific inhibitors and shRNAs of protein kinases, we observed that repression of ERK, JNK, p38, and NF-κB all inhibited HMGB1-induced cellular differentiation and migration of MC3T3-E1 cells. In addition, knocking down of advanced glycation end products (RAGE) but not Toll-like receptor (TLR)2 and TLR4 by shRNAs attenuated HMGB1-induced myofibroblast differentiation and migration. In conclusion, our study demonstrated that HMGB1 induced the fibrosis of osteoblasts in vitro via activating the RAGE-MAPK and NF-κB interaction signaling pathways.

High Mobility Group Box1 Inhibitor Glycyrrhizic Acid Attenuates Kidney Injury in Streptozotocin-Induced Diabetic Rats

“…The mitogen-activated protein kinase (MAPK) signalling pathways, including extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 MAPK, are a series of parallel cascades of serine/threonine kinases that are activated by extracellular HMGB1, which also results in the inflammatory response. It is worth mentioning that these inflammatory molecules, in turn, promote additional release of HMGB-1 from cells, resulting in a vicious cycle [8][9][10][11]. GA, also known as Glycyrrhizin, is a triterpenoid triterpene glycoside that is naturally extracted from the roots of licorice plants.…”

HMGB1 promotes bone fracture healing through activation of ERK signaling pathway in a rat tibial fracture model

“…Also, Zhang P et al reported that the activated ERK1/2 signaling pathway can elevate the expression of osteogenic genes ( Runx2 , ALP , COL1A1 , and OCN ) to facilitate osteoblast differentiation . More importantly, the transfection with siRNA HMGB1 for 30 or 60 nM has found by Qiu Y and his group to reduced JNK signaling pathways to inhibit cell differentiation and migration in mouse osteoblast‐like MC3T3‐E1 cells which were cultured in α‐MEM supplemented with 10% FBS and with 80 mg/mL enicillin and 80 mg/mL streptomycin . The in‐vitro investigation performed by Lin Feng et al also demonstrated that incubation with 25 ng/mL HMGB‐1 for 5 days can activate ERK signaling pathway to facilitate the secretion of osteoblast‐related genes (ALP and OCN) in MSCs which were cultured in basal culture medium supplemented with FBS, ultimately promoting osteoblast differentiation .…”

Notch signaling molecule is involved in the invasion of MiaPaCa2 cells induced by CoCl2 via regulating epithelial‑mesenchymal transition

“…Cellular metabolism associated with cell proliferation, anti-apoptosis, metastasis and resistance is abnormal in tumorigenesis, probably resulting from the regulation of Wnt/β-catenin pathway, mitogen-activated protein kinase signaling pathway and other signaling pathways, and hypoxia has an important role in this process ( 26 , 27 ). It has been reported that hypoxia is also able to maintain the characteristic of cancer stem cells and induce the progression of cancer cells ( 28 ).…”