Research Papers:

Estrogen/ERα signaling axis participates in osteoblast maturation via upregulating chromosomal and mitochondrial complex gene expressions

Pei-I Lin, Yu-Ting Tai, Wing P. Chan, Yi-Ling Lin, Mei-Hsiu Liao and Ruei-Ming Chen _

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Oncotarget. 2018; 9:1169-1186. https://doi.org/10.18632/oncotarget.23453

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Pei-I Lin1, Yu-Ting Tai2, Wing P. Chan3, Yi-Ling Lin2, Mei-Hsiu Liao1,2 and Ruei-Ming Chen1,2,4

1Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan

2Cell Physiology and Molecular Image Research Center and Department of Anesthesiology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan

3Department of Radiology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan

4Anesthesiology and Health Policy Research Center, Taipei Medical University Hospital, Taipei, Taiwan

Correspondence to:

Ruei-Ming Chen, email: [email protected]

Keywords: estrogen/ERα; osteoblast mineralization; ATP synthesis; genomic complex genes; mitochondrial COX I

Received: July 14, 2017    Accepted: December 09, 2017    Published: December 19, 2017


Estrogen deficiency usually leads to bone loss and osteoporosis in postmenopausal women. Osteoblasts play crucial roles in bone formation. However, osteoblast functions are influenced by mitochondrial bioenergetic conditions. In this study, we investigated the roles of the estrogen and estrogen receptor alpha (ERα) axis in mitochondrial energy metabolism and subsequent osteoblast mineralization. Exposure of rat calvarial osteoblasts to estradiol caused substantial improvements in alkaline phosphatase activities and cell calcification. In parallel, treatment of human osteoblast-like U2OS cells, derived from a female osteosarcoma patient, with estradiol specifically augmented ERα levels. Sequentially, estradiol stimulated translocation of ERα to nuclei in human osteoblasts and induced expressions of genomic respiratory chain complex NDUFA10, UQCRC1, cytochrome c oxidase (COX)8A, COX6A2, COX8C, COX6C, COX6B2, COX412, and ATP12A genes. Concurrently, estradiol stimulated translocation of ERα to mitochondria from the cytoplasm. A bioinformatic search found the existence of four estrogen response elements in the 5’-promoter region of the mitochondrial cox i gene. Interestingly, estradiol induced COX I mRNA and protein expressions in human osteoblasts or rat calvarial osteoblasts. Knocking-down ERα translation concurrently downregulated estradiol-induced COX I mRNA expression. Consequently, exposure to estradiol led to successive increases in the mitochondrial membrane potential, the mitochondrial enzyme activity, and cellular adenosine triphosphate levels. Taken together, this study showed the roles of the estradiol/ERα signaling axis in improving osteoblast maturation through upregulating the mitochondrial bioenergetic system due to induction of definite chromosomal and mitochondrial complex gene expressions. Our results provide novel insights elucidating the roles of the estrogen/ERα alliance in regulating bone formation.

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