Author(s): Poudel, Sunil
Date: 2023
Persistent ID: http://hdl.handle.net/10400.1/19664
Origin: Sapientia - Universidade do Algarve
Subject(s): Antioxidants; Pro-oxidants; Oxidative stress; Esveratrol; Mitotempo; Doxorubicin; Osteoblasts; Osteoclasts; Zebrafish; Seabream; Osteocrin; P53; Secondary osteoporosis
Osteoporosis is characterized by abnormal bone with low bone mass and degradation of skeleton microarchitecture, thus leading to bone fragility and risk of fracture. Oxidative stress induces an imbalance in osteoblast and osteoclast activity that leads to bone degradation, consequently resulting in osteoporotic phenotype. In addition, oxidative stress is a primary cause of secondary osteoporosis caused by specific medications. Understanding the role of oxidative stress in the development of primary and secondary osteoporosis could lead to further research towards preventive and therapeutic measures to combat this significant cause of mortality and morbidity worldwide. Antioxidant supplementation has improved bone mineral density and lowered the risk of fragility fractures. While it is not experimentally evident if the antioxidant activity is the cause of this alteration. Hence, this work aimed to counteract/rescue specific medication-induced secondary osteoporosis by supplementing antioxidants on in vitro and in vivo models. In addition, to provide insights into the molecular mechanisms on medication-induced bone impairment, the transcriptome of murine osteoblasts treated with antioxidants (Resveratrol and MitoTEMPO) and pro-oxidants (Doxorubicin) alone or in combination was analyzed. RNA-Seq data revealed that osteocrin and p53 are the responsible players on doxorubicin-induced bone impairment and its reversal by resveratrol. We further studied the effect of antioxidants and pro-oxidant on osteoclast differentiation, where we found out that doxorubicin also increased osteoclast differentiation. Based on our in vitro results, we confirm the effect of Resveratrol, MitoTEMPO on Doxorubicin-induced bone impairment with the zebrafish (osteocytic bone) and seabream (non-osteocytic bone) models. Our data indicate that regular supplementation of antioxidants effectively improves overall growth, mineralization and counteracts pro-oxidant induced bone pathologies on both models. In conclusion, this work proposes that the negative effect of the specific medication (i.e., Doxorubicin) can be reversed by regular supplementation of antioxidants (i.e., Resveratrol and MitoTEMPO). Furthermore, this work also proposes osteocrin as a key responsible factor for doxorubicin-induced bone impairment, and its reversal. Osteocrin can be further exploited as a communicator molecule for crosstalk between bone and other tissues.
