An acidic pH environment increases cell death and pro-inflammatory cytokine release in osteoblasts: The involvement of BAX Inhibitor-1

作者：Lee Geum Hwa; Hwang Jung Doo; Choi Je Yong; Park Hye Jeong; Cho Je Yoel; Kim Kyung Woon; Chae Han Jung^*; Kim Hyung Ryong

来源：International Journal of Biochemistry & Cell Biology, 2011, 43(9): 1305-1317.

DOI：10.1016/j.biocel.2011.05.004

• Cell death
• Osteoblasts
• Acidic pH
• Mitochondrial Ca(2+)
• BAX Inhibitor-1
• IL-1 beta
• IL-6
• TNF-alpha

BAX Inhibitor-1 (BI-1), a transmembrane protein on the endoplasmic reticulum, has been studied previously in various physic/pathological conditions, but not in bone cells. In this study, using the MG63 osteoblast cell line and osteoblasts differentiated from stem cells, the role of BI-1 was studied. First, expression of BI-1 was confirmed in osteoblasts, as well as osteoclasts, in mouse tibiae bone immunohistochemistry. For evaluation of a recently published property of BI-1, an acidic pH-dependent Ca(2+) channel-like effect in osteoblasts, acidic pH-associated cell death, and pro-inflammatory cytokine release were examined. In MG63 osteoblasts, acidic pH induced a pH-dependent increase in cell death and ER stress, as determined by elevated expression of GRP78, CHOP, phospho-elF2 alpha, IRE-1 alpha, spliced XBP-1, and phospho-JNK. In osteoblasts, mitochondrial Ca(2+) also showed a strong pH-dependent increase. BI-1 knock-down using siRNA protected cells against acidic pH, regulating mitochondrial Ca2+ accumulation, possibly via the acidic pH-dependent Ca(2+) channel-like effect of BI-1. BI-1 knock-down also resulted in inhibition of acidic pH-induced release of pro-inflammatory cytokines, including IL-1 beta, 1L-6, and TNF-alpha. In addition, bone marrow stem cells were differentiated into human osteoblasts, which showed increased expression of BI-1 mRNA and protein. In differentiated primary human osteoblasts, acidic pH-associated cell death, mitochondrial Ca(2+) accumulation, and pro-inflammatory cytokine release were more significant than in non-differentiated stem cells. In summary, endogenous expression of BI-1 is associated with acidic pH-induced Ca(2+) release, cell death, and pro-inflammatory cytokine release in human osteoblasts.

• 出版日期2011-9