Abstract
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.
Highlights
Osteoporosis, one of the most impactful metabolic diseases in the elderly, is called a silent disorder that is characterized by a decrease in the bone mineral density (BMD) and a T score of ≤ -2.5 [1]
This study demonstrated the participation of the estrogen/ERα signaling axis in regulation of osteoblast maturation possibly through stimulating mitochondrial bioenergetic metabolism
Maintenance of cellular Adenosine triphosphate (ATP) synthesis is essential for a dynamic balance between osteogenesis and osteoclastogenesis [26]
Summary
Osteoporosis, one of the most impactful metabolic diseases in the elderly, is called a silent disorder that is characterized by a decrease in the bone mineral density (BMD) and a T score of ≤ -2.5 [1]. Osteoporosis is attributed to multiple risk features, including genetics, lifestyle, the nutritional status, and personal and family histories. Among these factors, the aging-induced deficiency of estrogen, a major hormonal regulator of bone metabolism, plays a critical role in the pathophysiological incidence of osteoporosis [3]. Estrogen can improve bone formation by increasing osteoblast lifespans [6, 7]. An estrogen deficiency in postmenopausal women induces bone resorption but represses bone formation. Estrogen receptor alpha (ERα) functions as an effective receptor to transduce estrogen-induced messages in osteoblasts and osteoclasts [7]. The estrogen/ERα signaling pathway is essential for maintaining bone health
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