Increased NF-κB Activity and Decreased Wnt/β-Catenin Signaling Mediate Reduced Osteoblast Differentiation and Function in ΔF508 Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Mice

Hénaff, Carole Le; Mansouri, Rafik; Modrowski, Dominique; Zarka, Mylène; Geoffroy, Valérie; Marty, Caroline; Tarantino, Nadine; Laplantine, Emmanuel; Marie, Pierre J.

doi:10.1074/jbc.m115.646208

Cited by 37 publications

(28 citation statements)

References 46 publications

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“…Previous studies have implicated -catenin in the stabilization and cytoplasmic sequestration of p65NFB [32]. Wnt/ -catenin signalling plays a role in the regulation of osteoclast and osteoblast differentiation, and Sclerostin, a secreted inhibitor of Wnt/ -catenin signalling reduces bone formation [25][26][27]32]. In broad agreement with these findings, we showed that NFB inhibition by PTN in osteoblasts and osteoclasts was accompanied by a significant increase in -catenin activation and expression.…”

Section: Discussionsupporting

confidence: 90%

“…There is also evidence to suggest that NFB regulates osteoclast and osteoblast activity through its crosstalk with the Wnt/ -catenin pathway [23]. In osteoblasts, activation of -catenin stimulates bone formation and enhances the expression of runt related transcription factor 2 (Runx2), a key osteogenic factor essential for osteoblast differentiation [24][25][26][27]. Activation of -catenin inhibits osteoclast formation [28][29][30] and activation of NFB by RANKL in osteoclasts leads to -catenin inhibition [31,32].…”

Section: Introductionmentioning

confidence: 99%

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Pharmacological evidence for the bone-autonomous contribution of the NFκB/β-catenin axis to breast cancer related osteolysis

et al. 2017

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The NFκB signaling pathway is implicated in breast cancer and bone metastasis. However, the bone-autonomous contribution of NFκB to breast cancer-induced osteolysis is poorly understood. Here, we report that pretreatment of osteoblasts with the sesquiterpene lactone Parthenolide (PTN), a verified NFκB inhibitor, prior to exposure to conditioned medium from human and mouse breast cancer cell lines enhanced osteoblast differentiation and reduced osteoblast ability to stimulate osteoclastogenesis. PTN prevented breast cancer-induced osteoclast formation and reduced the ability of breast cancer cells to prolong osteoclast survival and to inhibit osteoclast apoptosis. In vivo, administration of PTN in immuno-competent mice reduced osteolytic bone loss and skeletal tumour growth following injection of the syngeneic 4T1-BT1 cells and reduced local osteolysis caused by conditioned medium from human and mouse osteotropic breast cancer cell lines. Mechanistic studies revealed that NFκB inhibition by PTN in osteoblasts and osteoclasts was accompanied by a significant increase in β-catenin activation and expression. Collectively, these results raise the possibility that combined targeting of NFκB and β-catenin signalling in the tumour microenvironment may be of value in the treatment of breast cancer related osteolysis.

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Pharmacological evidence for the bone-autonomous contribution of the NFκB/β-catenin axis to breast cancer related osteolysis

et al. 2017

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“…Consistent with our results, these studies also found increased β-catenin phosphorylation, reduced osteoblast β-catenin expression and altered expression of Wnt/β-catenin target genes in ΔF508 mutant osteoblasts. 39,40 Given that bone is of mesoderm origin, it is plausible that the defected mesoderm differentiation reported in our study contributes to the pathological condition of bone in ΔF508 mice. Collectively, in view of the importance of Wnt/β-catenin pathway in embryonic development, the presently demonstrated critical role of CFTR in regulating β-catenin signaling provides novel insights into the molecular mechanism underlying embryonic development.…”

Section: Discussionmentioning

confidence: 83%

CFTR- β -catenin interaction regulates mouse embryonic stem cell differentiation and embryonic development

et al. 2016

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Cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-regulated anion channel capable of conducting both Cl and HCO, mutations of which cause cystic fibrosis (CF), a common autosomal recessive disease. Although CF patients are known to have varied degree of developmental problems, the biological role of CFTR in embryonic development remains elusive. Here, we show that CFTR is functionally expressed in mouse ESCs. CFTR mESCs exhibit dramatic defect in mesendoderm differentiation. In addition, CFTR physically interacts with β-catenin, defect of which leads to premature degradation of β-catenin and suppressed activation of β-catenin signaling. Furthermore, knockdown of CFTR retards the early development of Xenopus laevis with impaired mesoderm/endoderm differentiation and β-catenin signaling. Our study reveals a previously undefined role of CFTR in controlling ESC differentiation and early embryonic development via its interaction with β-catenin, and provides novel insights into the understanding of embryonic development.

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“…Of the identified 1,900 mutations of CFTR in humans, deletion of the phenylalanine at position 508 (DF508) is the most frequent mutation found in CF patients, which results in a folding defect and endoplasmic reticulum associated degradation of CFTR [17]. It is being recently recognized that apart from transporting anions, CFTR is involved in other cellular functions, including inflammation [6,18], proliferation [19][20][21], and differentiation [22][23][24] in bronchial epithelia, granulosa cells, enterocytes, and osteoblasts. Several signaling molecules associated with CFTR have been reported, including MAPK and NF-κB [6,18,[25][26][27][28].…”

mentioning

confidence: 99%

Epidermal CFTR Suppresses MAPK/NF-κB to Promote Cutaneous Wound Healing

Chen

et al. 2016

Cell Physiol Biochem

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Background: CFTR is implicated in cutaneous wound healing although the underlying mechanisms are not fully understood. In other cell types, CFTR is reported to regulate MAPK/ NF-κB signaling. We undertook the present study to explore a possible role of CFTR in regulating MAPK/NF-κB during cutaneous wound healing. Methods& Results: The splint-excisional and incisional wound healing models were used in CFTR mutant (DF508) mice. The cell-scratch model was used in a human keratinocyte line, HaCaT, in conjunction with CFTR knockdown or overexpression. The epidermal inflammation, keratinocyte proliferation and differentiation, as well as MAPK/NF-κB signaling were examined. Inhibitors of MAPK/NF-κB were also used. Results: Both DF508 mice and HaCaT cells with CFTR knockdown exhibited delayed cutaneous wound healing with exuberant inflammation, increased proliferation and aberrant differentiation. Knockdown of CFTR in HaCaT cells resulted in phosphorylation of ERK, p38 and IκBα. The disturbance of inflammation, proliferation and differentiation in HaCaT cells were reversed by CFTR overexpression or inhibition of MAPK or NF-κB. Conclusion: CFTR plays a role in suppressing MAPK/NF-κB to relieve inflammation, reduce proliferation and promote differentiation of keratinocytes, and thus promotes cutaneous wound healing.

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Increased NF-κB Activity and Decreased Wnt/β-Catenin Signaling Mediate Reduced Osteoblast Differentiation and Function in ΔF508 Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Mice

Cited by 37 publications

References 46 publications

Pharmacological evidence for the bone-autonomous contribution of the NFκB/β-catenin axis to breast cancer related osteolysis

Pharmacological evidence for the bone-autonomous contribution of the NFκB/β-catenin axis to breast cancer related osteolysis

CFTR- β -catenin interaction regulates mouse embryonic stem cell differentiation and embryonic development

Epidermal CFTR Suppresses MAPK/NF-κB to Promote Cutaneous Wound Healing

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