The Polyphenol Fisetin Protects Bone by Repressing NF-κB and MKP-1-Dependent Signaling Pathways in Osteoclasts

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.

Design and development of dry powder sulfobutylether-β-cyclodextrin complex for pulmonary delivery of fisetin

“…It has shown synergistic activities with other anticancer agents (i.e. cisplatin and cyclophosphamide) in different carcinoma cell lines [2,3] and acts as an adjunct in cancer therapy to alleviate specific adverse effects related to cytotoxic agents or other therapeutics, including protection against ovariectomy-induced bone loss in mice [4] and has a renoprotective effect in cisplatininduced nephrotoxicity in rats [5].…”

Fisetin inhibits the growth and migration in the A549 human lung cancer cell line via the ERK1/2 pathway

“…At present, fisetin has shown multiple biological activities including anti-proliferative (7,8), pro-apoptotic (9-13), neuroprotective (14) and anti-oxidative activities (15). Moreover, fisetin has been shown to suppress the proliferation of a wide variety of tumor cell, including prostate cancer (16), liver cancer (17), colon cancer (18) and leukemia (19) cells, and inhibit the mitogen-activated protein kinase (MAPK) and nuclear factor (NF)-κB signaling pathways in various type of cancer cell, such as colon and pancreatic cancer (14,(20)(21)(22)(23)(24). Fisetin was also reported to reduce the invasive and migratory capacity of the A549 human lung cancer cell line via the extracellular signal-regulated kinase (ERK) signaling pathway (25).…”

How fisetin reduces the impact of age and disease on CNS function

“…The activation of the JNK and p38 MAPK pathways contributes to pro-inflammatory cytokine production (153, 154). A recent study showed that in RAW264.7 macrophages, fisetin suppresses both p38 MAPK and JNK activation by increasing the levels of MAPK phosphatase-1 (MKP-1), an enzyme responsible for p38 MAPK and JNK dephosphorylation (155). Fisetin increases MKP-1 levels by a post-translational mechanism involving the inhibition of its ubiquitination and subsequent targeting to the proteasome (155).…”

“…A recent study showed that in RAW264.7 macrophages, fisetin suppresses both p38 MAPK and JNK activation by increasing the levels of MAPK phosphatase-1 (MKP-1), an enzyme responsible for p38 MAPK and JNK dephosphorylation (155). Fisetin increases MKP-1 levels by a post-translational mechanism involving the inhibition of its ubiquitination and subsequent targeting to the proteasome (155). Interestingly, it has been shown that ERK activation (see section 5.3) can promote MKP-1 stabilization via this pathway (155).…”

“…Fisetin increases MKP-1 levels by a post-translational mechanism involving the inhibition of its ubiquitination and subsequent targeting to the proteasome (155). Interestingly, it has been shown that ERK activation (see section 5.3) can promote MKP-1 stabilization via this pathway (155). …”