Arsenic induces cell apoptosis in cultured osteoblasts through endoplasmic reticulum stress.
Osteoporosis is characterized by low bone mass resulting from an imbalance between bone resorption by osteoclasts and bone formation by osteoblasts. Therefore, decreased bone formation by osteoblasts may lead to the development of osteoporosis, and rate of apoptosis is responsible for the regulation of bone formation. Arsenic (As) exists ubiquitously in our environment and increases the risk of neurotoxicity, liver injury, peripheral vascular disease and cancer. However, the effect of As on apoptosis of osteoblasts is mostly unknown. Here, we found that As induced cell apoptosis in osteoblastic cell lines (including hFOB, MC3T3-E1 and MG-63) and mouse bone marrow stromal cells (M2-10B4). As also induced upregulation of Bax and Bak, downregulation of Bcl-2 and dysfunction of mitochondria in osteoblasts. As also triggered endoplasmic reticulum (ER) stress, as indicated by changes in cytosolic-calcium levels. We found that As increased the expression and activities of glucose-regulated protein 78 (GRP78) and calpain. Transfection of cells with GRP78 or calpain siRNA reduced As-mediated cell apoptosis in osteoblasts. Therefore, our results suggest that As increased cell apoptosis in cultured osteoblasts and increased the risk of osteoporosis.
Tang
Chih-Hsin
CH
Department of Pharmacology, China Medical University, Taichung, Taiwan. chtang@mail.cmu.edu.tw
Chiu
Yung-Cheng
YC
Huang
Chun-Fa
CF
Chen
Ya-Wen
YW
Chen
Po-Chun
PC
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D000077237:Arsenic Trioxide; D001152:Arsenicals; D002154:Calpain / Q000096:biosynthesis; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D019254:Genes, bcl-2 / Q000187:drug effects; D006360:Heat-Shock Proteins / Q000096:biosynthesis; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D010006:Osteoblasts / Q000187:drug effects* / Q000378:metabolism; D010087:Oxides / Q000633:toxicity*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis*; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000096:biosynthesis; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis
D001152:Arsenicals; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D010087:Oxides; D019253:Proto-Oncogene Proteins c-bcl-2; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D002154:Calpain; D000077237:Arsenic Trioxide