Fisetin Inhibits Osteoclast Differentiation via Downregulation of p38 and c-Fos-NFATc1 Signaling Pathways

Choi, Sik‐Won; Son, Young–Jin; Yun, Jung‐Mi; Kim, Seong Hwan

doi:10.1155/2012/810563

Cited by 38 publications

(32 citation statements)

References 37 publications

(38 reference statements)

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“…In vitro, RelB +/+ BMMs upregulate NFATc1, a master transcription regulator of osteoclastogenesis, during culture with RANKL, but RelB –/– do not, suggesting that RelB is upstream of NFATc1. Other studies have successfully used NFATc1 to rescue differentiation defects in OCs to study the effect of molecules independent from differentiation . Therefore, to understand the dependence of mitochondrial biogenesis on differentiation, we tried to rescue RelB –/– differentiation in vitro by retroviral overexpression of NFATc1.…”

Section: Resultsmentioning

confidence: 99%

Alternative NF-κB Regulates RANKL-Induced Osteoclast Differentiation and Mitochondrial Biogenesis via Independent Mechanisms

Zeng

Faccio

Novack

2015

Journal of Bone and Mineral Research

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Mitochondrial biogenesis, the generation of new mitochondrial DNA and proteins, has been linked to osteoclast (OC) differentiation and function. In this study we used mice with mutations in key alternative NF-κB pathway proteins, RelB and NIK, to dissect the complex relationship between mitochondrial biogenesis and osteoclastogenesis. OC precursors lacking either NIK or RelB, RANKL were unable to increase mitochondrial DNA or OxPhos protein expression, associated with lower oxygen consumption rates. Transgenic OC precursors expressing constitutively active NIK showed normal RANKL-induced mitochondrial biogenesis (OxPhos expression and mitochondria copy number) compared to controls, but larger mitochondrial dimensions and increased oxygen consumption rates, suggesting increased mitochondrial function. To deduce the mechanism for mitochondrial biogenesis defects in NIK- and RelB-deficient precursors, we examined expression of genes known to control this process. PGC-1β (Ppargc1b) expression, but not PGC-1α, PPRC1 or ERRα, was significantly reduced in RelB−/− and NIK−/− OCs. Because PGC-1β has been reported to positively regulate both mitochondrial biogenesis and differentiation in OCs, we retrovirally overexpressed PGC-1β in RelB−/− cells, but surprisingly found that it did not affect differentiation, nor restore RANKL-induced mitochondrial biogenesis. To determine whether the blockade in osteoclastogenesis in RelB-deficient cells precludes mitochondrial biogenesis, we rescued RelB−/− differentiation via overexpression of NFATc1. Mitochondrial parameters in neither WT nor RelB-deficient cultures were affected by NFATc1 overexpression, and bone resorption in RelB −/− was not restored. Furthermore, NFATc1 co-overexpression with PGC-1β, while allowing OC differentiation, did not rescue mitochondrial biogenesis or bone resorption in RelB−/− OCs, by CTX-I levels. Thus, our results indicate that the alternative NF-κB pathway plays dual, but distinct roles in controlling the independent processes of OC differentiation and OC mitochondrial biogenesis. Furthermore, the inability of PGC-1β to drive mitochondrial biogenesis in OCs without RelB indicates a cell-type specificity in mitochondria regulation.

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Section: Resultsmentioning

confidence: 99%

Alternative NF-κB Regulates RANKL-Induced Osteoclast Differentiation and Mitochondrial Biogenesis via Independent Mechanisms

Zeng

Faccio

Novack

2015

Journal of Bone and Mineral Research

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“…While we were preparing the manuscript, Choi et al [41] and Sakai et al [42] published their work about fisetin action on osteoclast differentiation. As demonstrated in our study, they both show that fisetin dose-dependently inhibits the osteoclast differentiation by repressing the RANKL-induced c-Fos and NFATc transcription factors and osteoclasts markers expressions, thus corroborating our results on the potential of fisetin on osteoclastogenesis.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2013

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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.

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“…BMMs were isolated as previously described (Choi et al, 2012). In detail, after cervical dislocation, bone marrow cells (BMCs) were obtained from 5-week-old male ICR mice (Damool Science, Daejeon, Korea) by flushing femurs and tibias with α-MEM supplemented with antibiotics (100 units/ml penicillin and 100 μg/ml streptomycin; Invitrogen Life Technologies, CA).…”

Section: Methodsmentioning

confidence: 99%

Osteoporotic bone of miR-150-deficient mice: Possibly due to low serum OPG-mediated osteoclast activation

et al. 2015

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MicroRNA (miR)-150 has been shown to control B and T cell differentiation in the bone marrow. The regulation of B and T cells is directly or systematically associated with bone remodeling cells such as osteoclasts; however, the functional role of miR-150 in bone homeostasis has not been well studied. Here, we observed down-regulation of miR-150 during in vitro osteoclast differentiation and, furthermore, that miR-150 knockout mice exhibit decreased bone mass and an increased number of osteoclasts. miR-150 deficiency did not affect osteoclast differentiation, but miR150 knockout mice had significantly lower osteoprotegrin (OPG) serum levels, suggesting that the reduction of serum OPG level in miR-150 knockout mice might induce B cell expansion and subsequently increase serum levels of immunoglobulins for activating osteoclast differentiation.

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Fisetin Inhibits Osteoclast Differentiation via Downregulation of p38 and c-Fos-NFATc1 Signaling Pathways

Cited by 38 publications

References 37 publications

Alternative NF-κB Regulates RANKL-Induced Osteoclast Differentiation and Mitochondrial Biogenesis via Independent Mechanisms

Alternative NF-κB Regulates RANKL-Induced Osteoclast Differentiation and Mitochondrial Biogenesis via Independent Mechanisms

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

Osteoporotic bone of miR-150-deficient mice: Possibly due to low serum OPG-mediated osteoclast activation

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