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The polyphenol fisetin protects bone by repressing NF-κB and MKP-1-dependent signaling pathways in osteoclasts
Laurent Léotoing1, Fabien Wauquier, Jérôme Guicheux
1Clermont Université, Université d'Auvergne, Clermont-Ferrand, France.
Abstract:
Osteoporosis is a bone pathology leading to increase fractures risk and challenging quality of life. Since current treatments could exhibit deleterious side effects, the use of food compounds derived from plants represents a promising innovative alternative due to their potential therapeutic and preventive activities against human diseases. In this study, we investigated the ability of the polyphenol fisetin to counter osteoporosis and analyzed the cellular and molecular mechanisms involved. In vivo, fisetin consumption significantly prevented bone loss in estrogen deficiency and inflammation mice osteoporosis models. Indeed, bone mineral density, micro-architecture parameters and bone markers were positively modulated by fisetin. Consistent with in vivo results, we showed that fisetin represses RANKL-induced osteoclast differentiation and activity as demonstrated by an inhibition of multinucleated cells formation, TRAP activity and differentiation genes expression. The signaling pathways NF-κB, p38 MAPK, JNK and the key transcription factors c-Fos and NFATc1 expressions induced by RANKL, were negatively regulated by fisetin. We further showed that fisetin inhibits the constitutive proteasomal degradation of MKP-1, the phosphatase that deactivates p38 and JNK. Consistently, using shRNA stable cell lines, we demonstrated that impairment of MKP-1 decreases fisetin potency. Taken together, these results strongly support that fisetin should be further considered as a bone protective agent.
Insights
The natural compound fisetin prevents bone loss in osteoporosis models by inhibiting osteoclast activity and regulating key signaling pathways. This polyphenol shows promise as a bone-protective agent, offering a potential alternative to current treatments.
Area of Science:
- Biochemistry
- Cell Biology
- Pharmacology
Background:
- Osteoporosis leads to increased fracture risk and reduced quality of life.
- Current osteoporosis treatments may have adverse side effects.
- Plant-derived compounds offer a promising alternative for disease prevention and treatment.
Purpose of the Study:
- To investigate the efficacy of the polyphenol fisetin in preventing osteoporosis.
- To elucidate the cellular and molecular mechanisms underlying fisetin's bone-protective effects.
Main Methods:
- In vivo studies using estrogen deficiency and inflammation-induced osteoporosis mouse models.
- Assessment of bone mineral density, micro-architecture, and bone markers.
- In vitro analysis of osteoclast differentiation, activity, and related signaling pathways (NF-κB, MAPK, c-Fos, NFATc1).
- Investigation of fisetin's effect on MKP-1 (a phosphatase) and its interaction with signaling pathways.
Main Results:
- Fisetin consumption significantly prevented bone loss and improved bone parameters in vivo.
- Fisetin repressed RANKL-induced osteoclast differentiation and activity in vitro.
- Fisetin negatively regulated key signaling pathways (NF-κB, p38 MAPK, JNK) and transcription factors (c-Fos, NFATc1).
- Fisetin inhibited the proteasomal degradation of MKP-1, enhancing its bone-protective effects.
Conclusions:
- Fisetin demonstrates significant bone-protective effects in osteoporosis models.
- Fisetin acts by inhibiting osteoclastogenesis and modulating crucial cellular signaling pathways.
- Fisetin's mechanism involves stabilizing MKP-1, suggesting its potential as a therapeutic agent for osteoporosis.
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