Methylpiperidinopyrazole Attenuates Estrogen-Induced Mitochondrial Energy Production and Subsequent Osteoblast Maturation via an Estrogen Receptor Alpha-Dependent Mechanism.

Poh-Shiow Yeh,Shun-Tai Yang,Jui-Tai Chen,Yih-Giun Cherng,Yu-Ting Tai,Ruei-Ming Chen

doi:10.3390/molecules25122876

Abstract

An estrogen deficiency is the main cause of osteoporosis in postmenopausal women. In bone remodeling, estrogen receptors (ERs) can mediate estrogen-transducing signals. Methylpiperidinopyrazole (MPP) is a highly specific antagonist of ER-alpha (ERα). This study was designed to evaluate the effects of MPP on estrogen-induced energy production, subsequent osteoblast maturation, and the possible mechanisms. Exposure of primary osteoblasts isolated from neonatal rat calvarias to MPP did not affect cell morphology or survival. Estradiol can induce translocation of ERα into mitochondria from the cytoplasm. Interestingly, pretreatment of rat calvarial osteoblasts with MPP lowered estrogen-induced ERα translocation. Sequentially, estrogen-triggered expressions of mitochondrial energy production-linked cytochrome c oxidase (COX) I and COX II messenger (m)RNAs were inhibited following pretreatment with MPP. Consequently, MPP caused decreases in estrogen-triggered augmentation of the activities of mitochondrial respiratory complex enzymes and levels of cellular adenosine phosphate (ATP). During progression of osteoblast maturation, estrogen induced bone morphogenetic protein (BMP)-6 and type I collagen mRNA expressions, but MPP treatment inhibited such induction. Consequently, estrogen-induced osteoblast activation and mineralization were attenuated after exposure to MPP. Taken together, MPP suppressed estrogen-induced osteoblast maturation through decreasing chromosomal osteogenesis-related BMP-6 and type I collagen mRNA expressions and mitochondrial ATP synthesis due to inhibiting energy production-linked COX I and II mRNA expressions. MPP can appropriately be applied to evaluate estrogen-involved bioenergetics and osteoblast maturation.

Highlights

Osteoporosis, a chronic and age-related bone disorder, occurs because of continual loss of bone mass [1]
This study successfully isolated rat calvarial osteoblasts as our experimental model to evaluate the effects of MPP on osteoblast maturation and the possible mechanisms
Exposure of rat calvarial osteoblasts to MPP did not lead to cytotoxicity but significantly lowered estradiol-induced translocation of ERα from the cytoplasm to mitochondria

Summary

Introduction

Osteoporosis, a chronic and age-related bone disorder, occurs because of continual loss of bone mass [1]. The quality of bone is maintained through bone remodeling, a dynamic process that is a balance between osteoblast-mediated bone formation and osteoclast-involved bone resorption [2]. An imbalance of bone remodeling can lead to bone diseases such as osteoporosis, osteopenia, and Paget’s disease. Both women and men over the age of 50 years may suffer from osteoporosis at 1:3 and 1:5 ratios, respectively [3]. A reduction in levels of serum estrogen is frequently associated with elevated activities of osteoclasts, resulting in faster bone resorption than formation and ultimate loss of bone mass [5]. Estrogen plays critical roles in maintaining bone remodeling and bone mass

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Discussion

Conclusion