Fas- and Mitochondria-Mediated Signaling Pathway Involved in Osteoblast Apoptosis Induced by AlCl3

Abstract

Aluminum (Al) is known to induce apoptosis of osteoblasts (OBs). However, the mechanism is not yet established. To investigate the apoptotic mechanism of OBs induced by aluminum trichloride (AlCl), the primary OBs from the craniums of fetal Wistar rats were exposed to 0 mg/mL (control group, CG), 0.06 mg/mL (low-dose group, LG), 0.12 mg/mL (mid-dose group, MG), and 0.24 mg/mL (high-dose group, HG) AlCl for 24 h, respectively. We observed that AlCl induced OB apoptosis with the appearance of apoptotic morphology and increase of apoptosis rate. Additionally, AlCl treatment activated mitochondrial-mediated signaling pathway, accompanied by mitochondrial membrane potential (ΔΨm) depolarization, release of cytochrome c from the mitochondria to the cytoplasm, as well as survival signal-related factor caspase-9 and caspase-3 activation. AlCl exposure also activated Fas/Fas ligand signaling pathway, presented as Fas, Fas ligand, and Fas-associated death domain expression enhancement and caspase-8 activation, as well as the hydrolysis of Bid to truncated Bid, suggesting that the Fas-mediated signaling pathway might aggravate mitochondria-mediated OB apoptosis through hydrolyzing Bid. Furthermore, AlCl exposure inhibited Bcl-2 protein expression and increased the expressions of Bax, Bak, and Bim in varying degrees. These results indicated that AlCl exposure induced OB apoptosis through activating Fas- and mitochondria-mediated signaling pathway and disrupted B-cell lymphoma-2 family proteins.

Aluminium toxicosis: a review of toxic actions and effects

“…Immune functions of splenic B-and T-lymphocytes were inhibited in vitro by reduction of lymphocyte proliferation, cytokine secretion and proportions of CD-3(+) and CD-4(+) lymphocytes . LPS-induced NLRP3 inflammasome activation, IL-1β, IL-6 and TNF-α expression and release in peritoneal macrophages were also suppressed by Al exposure (Xu et al, 2018). Norepinerphrine release and activation of β-adenoceotors/cAMP pathway were promoted by Al in vivo, and this endocrine factor suppressed macrophage expressions of MIF and TNF-α (Zhuang et al, 2016).…”

“…Oxidative stress, lipid peroxidation Kattab et al, 2010;Exley, 2013;Abd-Elhady et al, 2013;Zhang et al, 2016;Yang et al, 2018;Yu et al, 2019 Pro-inflammatory: organ inflammation in lung, intestine, heart, and testis Fogarty et al, 1998;Verma et al, 2007;Lerner, 2007;Exley, 2013;Taiwo, 2014;de Chambrun et al, 2014;Gherardi et al, 2016;Martinez et al, 2017;Hangouche et al, 2017 Immunosupression: induces lymphocyte apoptosis and dysfunction, inhibits lymphocyte proliferation, causes macrophage dysfunction Nordal and Dahl, 1988;Kammalov et al, 2011;She et al, 2012;Zhu et al, 2014;Zhuang et al, 2016;Xu et al, 2018;Yu et al, 2019 Protein denaturation and transformation Exley et al, 2006;Mujika et al, 2018 Enzymatic stimulation or inhibition Ohsaka and Nomura, 2016 Metabolic impairment: impairs glycolysis and Kreb's cycle; promotes lipid and protein oxidation Xu et al 1990;Mailloux et al, 2006 Genotoxicity: reduced cell proliferation and differentiation, dysneurogenesis Nam et al, 2014 Amyloidogenic and anti-amyloidolytic Sakamoto et al, 2006;Xu et al, 2016 Acts as metalloestrogen, promotes proliferation and migration of breast cancer cells Bakir and Darbre, 2015;Darbre, 2016 Induces teratogenesis causing foetal and neonatal defects Malekshah et al, 2005;Wang et al, 2012;El Mazoudy and Bekhet, 2016 Disrupts mineral metabolism of Fe, P, Ca, Zn, Cu by altering intestinal absorption and cellular uptake…”

“…Iron overload due to Al exposure has been shown to result in increased lipid peroxidation, DNA lesions, and apoptosis induced by reactive oxygen species (Bacon et al, 1983;Oteiza, 1994;Kell, 2009). Apoptosis of erythrocytes (eryptosis), lymphocytes and osteoblasts is also stimulated by Al ions (Niemoeller et al, 2006;Li et al, 2012;Xu et al, 2018;Yang et al, 2018;Yu et al, 2019). The oxidative injury was reported to activate the JNK apoptotic pathway in ostoblasts (Yang et al, 2018).…”

“…The oxidative injury was reported to activate the JNK apoptotic pathway in ostoblasts (Yang et al, 2018). In culture, Al induced apoptosis of osteoblasts by inhibiting apoptotic Bcl-2 protein expression and increasing the expression of pro-apoptotic Bax, Bak and Bim proteins (Xu et al, 2018). Al may decrease ferritin synthesis and increase the expression of transferrin receptors, thereby disrupting the normal synthesis of transferrin receptors with ferritin creating increased free iron levels in the cell, resulting in an increase of oxidative damage via the fenton reaction (Yamanaka et al, 1999).…”

MiRNAs in Radiotherapy Resistance of Nasopharyngeal Carcinoma

“…It is well known that Fas, also known as APO-1, TNFR (tumor necrosis factor receptor) and the NGF receptor family can drive cells to pass the Caspase pathway when they bind to their receptors [56]. Caspases belong to cysteine proteases and are a key enzyme that causes apoptosis.…”