Reversal of Doxorubicin-Induced Bone Loss and Mineralization by Supplementation of Resveratrol and MitoTEMPO in the Early Development of Sparus aurata.

Sunil Poudel,Maria Leonor Cancela,Marisol Izquierdo,Paulo J Gavaia

doi:10.3390/nu14061154

Abstract

Doxorubicin is a widely used chemotherapeutic drug known to induce bone loss. The mechanism behind doxorubicin-mediated bone loss is unclear, but oxidative stress has been suggested as a potential cause. Antioxidants that can counteract the toxic effect of doxorubicin on the bone would be helpful for the prevention of secondary osteoporosis. We used resveratrol, a natural antioxidant, and MitoTEMPO, a mitochondria-targeted antioxidant, to counteract doxorubicin-induced bone loss and mineralization on Sparus aurata larvae. Doxorubicin supplemented Microdiets increased bone deformities, decreased mineralization, and lipid peroxidation, whereas Resveratrol and MitoTEMPO supplemented microdiets improved mineralization, decreased bone deformities, and reversed the effects of doxorubicin in vivo and in vitro, using osteoblastic VSa13 cells. Partial Least-Squares Discriminant Analysis highlighted differences between groups on the distribution of skeletal anomalies and mineralization of skeleton elements. Calcium and Phosphorus content was negatively affected in the doxorubicin supplemented group. Doxorubicin reduced the mRNA expression of antioxidant genes, including catalase, glutathione peroxidase 1, superoxide dismutase 1, and hsp90 suggesting that ROS are central for Doxorubicin-induced bone loss. The mRNA expression of antioxidant genes was significantly increased on resveratrol alone or combined treatment. The length of intestinal villi was increased in response to antioxidants and reduced on doxorubicin. Antioxidant supplements effectively prevent bone deformities and mineralization defects, increase antioxidant response and reverse doxorubicin-induced effects on bone anomalies, mineralization, and oxidative stress. A combined treatment of doxorubicin and antioxidants was beneficial in fish larvae and showed the potential for use in preventing Doxorubicin-induced bone impairment.

Highlights

Oxidative stress is caused by reactive oxygen species (ROS) that are normally generated as by-products of aerobic metabolism during oxidative phosphorylation in mitochondria [1]
The aims of this study were to investigate the effects of doxorubicin, resveratrol, and MitoTEMPO on bone development and mineralization and to determine the capacity of antioxidants to counteract the potentially negative effects of doxorubicin on the developing skeleton of Sparus aurata
No significant differences were observed in other groups

Summary

Introduction

Oxidative stress is caused by reactive oxygen species (ROS) that are normally generated as by-products of aerobic metabolism during oxidative phosphorylation in mitochondria [1]. The major forms of ROS include the superoxide anions (O2−), hydrogen peroxide (H2O2), and free radicals such as hydroxyl radicals (OH). Oxidative stress caused by ROS alters the bone remodeling process, causing an unbalance between osteoclast and osteoblast activity [2]. This can lead to metabolic bone diseases and contribute to the pathogenesis of skeletal system disorders including osteoporosis, characterized by low bone mineral density, decrease in bone mass and density, and deterioration of bone structure, which causes bone fragility and risk of fracture [3,4]. Osteoporosis can be classified into various types: primary osteoporosis or idiopathic osteoporosis, age-related osteoporosis, and secondary osteoporosis, where bone loss results from a specific disease or medication [4]

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