PUBLICATION
Resveratrol-Mediated Reversal of Doxorubicin-Induced Osteoclast Differentiation
- Authors
- Poudel, S., Martins, G., Cancela, M.L., Gavaia, P.J.
- ID
- ZDB-PUB-221212-9
- Date
- 2022
- Source
- International Journal of Molecular Sciences 23(23): (Journal)
- Registered Authors
- Cancela, Leonor
- Keywords
- MitoTEMPO, doxorubicin, osteoclast differentiation, oxidative stress, resveratrol, secondary osteoporosis
- MeSH Terms
-
- Animals
- Antioxidants/metabolism
- Antioxidants/pharmacology
- Bone Resorption*/metabolism
- Cell Differentiation
- Doxorubicin/adverse effects
- Doxorubicin/metabolism
- NFATC Transcription Factors/metabolism
- Osteoclasts/metabolism
- Osteogenesis
- RANK Ligand/metabolism
- Resveratrol/metabolism
- Resveratrol/pharmacology
- Zebrafish*/metabolism
- PubMed
- 36499492 Full text @ Int. J. Mol. Sci.
Citation
Poudel, S., Martins, G., Cancela, M.L., Gavaia, P.J. (2022) Resveratrol-Mediated Reversal of Doxorubicin-Induced Osteoclast Differentiation. International Journal of Molecular Sciences. 23(23):.
Abstract
Secondary osteoporosis has been associated with cancer patients undertaking Doxorubicin (DOX) chemotherapy. However, the molecular mechanisms behind DOX-induced bone loss have not been elucidated. Molecules that can protect against the adverse effects of DOX are still a challenge in chemotherapeutic treatments. We investigated the effect and mechanism of DOX in osteoclast differentiation and used the Sirt 1 activator resveratrol (RES) to counteract DOX-induced effects. RAW 264.7 cells were differentiated into osteoclasts under cotreatment with DOX and RES, alone or combined. RES treatment inhibited DOX-induced osteoclast differentiation, reduced the expression of osteoclast fusion marker Oc-stamp and osteoclast differentiation markers Rank, Trap, Ctsk and Nfatc1. Conversely, RES induced the upregulation of antioxidant genes Sod 1 and Nrf 2 while DOX significantly reduced the FoxM1 expression, resulting in oxidative stress. Treatment with the antioxidant MitoTEMPO did not influence DOX-induced osteoclast differentiation. DOX-induced osteoclastogenesis was studied using the cathepsin-K zebrafish reporter line (Tg[ctsk:DsRed]). DOX significantly increased ctsk signal, while RES cotreatment resulted in a significant reduction in ctsk positive cells. RES significantly rescued DOX-induced mucositis in this model. Additionally, DOX-exposed zebrafish displayed altered locomotor behavior and locomotory patterns, while RES significantly reversed these effects. Our research shows that RES prevents DOX-induced osteoclast fusion and activation in vitro and in vivo and reduces DOX-induced mucositis, while improving locomotion parameters.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping