Canonical Wnt signaling inhibits osteoclastogenesis independent of osteoprotegerin

Albers, Joachim; Keller, Johannes; Baranowsky, Anke; Beil, Frank Timo; Catalá-Lehnen, Philip; Schulze, Jochen; Amling, Michael; Schinke, Thorsten

doi:10.1083/jcb.201207142

Cited by 161 publications

(137 citation statements)

References 39 publications

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“…S2). This is striking given that canonical Wnt signaling inhibits osteoclast differentiation and promotes osteoblast-mediated inhibition of osteoclastogenesis (Albers et al , 2013; Glass et al , 2005; Spencer et al , 2006). …”

Section: Resultsmentioning

confidence: 99%

“…Loss of β-catenin in mesencymal progenitors and inactivation of Lrp5, one of the Wnt coreceptor, prevents osteoblast differentiation resulting in low bone mass (Gong et al , 2001; Kato et al , 2002). Moreover, Wnt activation in differentiated osteoblasts promotes the ability of osteoblast to inhibit osteoclast differentiation and their activity (Albers et al , 2013; Glass et al , 2005; Spencer et al , 2006). Disruption of the well-tuned balance of the production of bone matrix by osteoblasts, and the resorption by osteoclast causes disorders such as osteoporosis (Baron and Kneissel, 2013).…”

Section: Introductionmentioning

confidence: 99%

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Epithelium-Derived Wnt Ligands Are Essential for Maintenance of Underlying Digit Bone

Takeo

Hale

Ito

2016

Journal of Investigative Dermatology

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Clinically, many nail disorders accompany bone deformities, but whether the two defects are causally related is under debate. To investigate the potential interactions between the two tissue types, we analyzed epithelial-specific β-catenin deficient mice, in which nail differentiation is abrogated. These mice showed regression of not only the nail plate but also of the underlying digit bone. Characterization of these bone defects revealed active bone resorption, which is suppressed by Wnt activation in osteoblast and osteoclast precursors. Furthermore, we found that Wntless (Wls) expression, essential for Wnt ligand secretion, was lacking in the β-catenin deficient nail epithelium and that genetic deletion of Wls in the nail epithelium led to the lack of Wnt activation in osteoblast and osteoclast precursors and subsequently led to defective regression of the underlying digit bone. Together, these data show epithelial Wnt ligands can ultimately regulate Wnt signaling in osteoblasts and osteoclast precursors, known to regulate bone homeostasis. These results reveal a critical role for the nail epithelium on the digit bone during homeostatic regeneration and show that Wnt/β-catenin signaling is critical for this interaction.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Epithelium-Derived Wnt Ligands Are Essential for Maintenance of Underlying Digit Bone

Takeo

Hale

Ito

2016

Journal of Investigative Dermatology

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“…Moreover, we have shown that Ifrd1 deficiency attenuates the interaction between ␤-catenin and HDAC1, subsequently increasing the acetylation of ␤-catenin at K49 and leading to accumulation in the nucleus and activation of ␤-catenin-dependent transcription of Opg in osteoblasts (10). ␤-Catenin controls osteoclastogenesis (37,38); thus, it would be worth investigating whether Ifrd1 controls osteoclastogenesis by regulating ␤-catenin-dependent transcription, as observed in osteoblasts.…”

Section: Discussionmentioning

confidence: 97%

Transcriptional Modulator Ifrd1 Regulates Osteoclast Differentiation through Enhancing the NF-κB/NFATc1 Pathway

Iezaki

Fukasawa

Park

et al. 2016

Molecular and Cellular Biology

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Bone homeostasis is maintained by the synergistic actions of bone-resorbing osteoclasts and bone-forming osteoblasts. Here, we show that the transcriptional coactivator/repressor interferon-related developmental regulator 1 (Ifrd1) is expressed in osteoclast lineages and represents a component of the machinery that regulates bone homeostasis. Ifrd1 expression was transcriptionally regulated in preosteoclasts by receptor activator of nuclear factor B (NF-B) ligand (RANKL) through activator protein 1. Global deletion of murine Ifrd1 increased bone formation and decreased bone resorption, leading to a higher bone mass. Deletion of Ifrd1 in osteoclast precursors prevented RANKL-induced bone loss, although no bone loss was observed under normal physiological conditions. RANKL-dependent osteoclastogenesis was impaired in vitro in Ifrd1-deleted bone marrow macrophages (BMMs). Ifrd1 deficiency increased the acetylation of p65 at residues K122 and K123 via the inhibition of histone deacetylase-dependent deacetylation in BMMs. This repressed the NF-B-dependent transcription of nuclear factor of activated T cells, cytoplasmic 1 (NFATc1), an essential regulator of osteoclastogenesis. These findings suggest that an Ifrd1/NF-B/NFATc1 axis plays a pivotal role in bone remodeling in vivo and represents a therapeutic target for bone diseases.

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“…Wnt3a is known to play a critical role in the skeletal system, including in inflammatory processes, bone formation, and bone resorption [10,11,18,19]. In particular, Wnt3a is an important responder to mechanical stimulation by activating canonical Wnt signaling [20,21].…”

Section: Discussionmentioning

confidence: 99%

“…Although the involvement of Wnt/β-catenin signaling in osteoblast development has been characterized [2,4,9], the role of Wnt3a in the regulation of bone-resorbing osteoclasts is not fully understood. While some have reported that Wnt3a attenuates osteoclast development [10,11], others have found that it has little effect on osteoclastogenesis [6]. Using both mouse bone marrow cells and RAW264.7 pre-osteoclast cells, we examined the effects and regulatory mechanism of Wnt3a-driven regulation of osteoclast development.…”

Section: Introductionmentioning

confidence: 99%

Predicting and validating the pathway of Wnt3a-driven suppression of osteoclastogenesis

Hamamura

Chen

Nishimura

et al. 2014

Cellular Signalling

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Wnt signaling plays a major role in bone homeostasis and mechanotransduction, but its role and regulatory mechanism in osteoclast development are not fully understood. Through genome-wide in silico analysis, we examined Wnt3a-driven regulation of osteoclast development. Mouse bone marrow-derived cells were incubated with RANKL in the presence and absence of Wnt3a. Using microarray mRNA expression data, we conducted principal component analysis and predicted transcription factor binding sites (TFBSs) that were potentially involved in the responses to RANKL and Wnt3a. The principal component analysis predicted potential Wnt3a responsive regulators that would reverse osteoclast development, and a TFBS prediction algorithm indicated that the AP1 binding site would be linked to Wnt3a-driven suppression. Since c-Fos was upregulated by RANKL and downregulated by Wnt3a in a dose-dependent manner, we examined its role using RNA interference. The partial silencing of c-Fos suppressed RANKL-driven osteoclastogenesis by downregulating NFATc1, a master transcription factor of osteoclast development. Although the involvement of c-Myc was predicted and partially silencing c-Myc slightly reduced the level of TRAP, c-Myc silencing did not alter the expression of NFATc1. Collectively, the presented systems-biology approach demonstrates that Wnt3a attenuates RANKL-driven osteoclastogenesis by blocking c-Fos expression and suggests that mechanotransduction of bone alters the development of not only osteoblasts but also osteoclasts through Wnt signaling.

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Canonical Wnt signaling inhibits osteoclastogenesis independent of osteoprotegerin

Abstract: Canonical Wnt signaling through Fzd8 and β-catenin negatively regulates osteoclast differentiation and reduces bone resorption independent of osteoprotegerin.

Cited by 161 publications

References 39 publications

Epithelium-Derived Wnt Ligands Are Essential for Maintenance of Underlying Digit Bone

Epithelium-Derived Wnt Ligands Are Essential for Maintenance of Underlying Digit Bone

Transcriptional Modulator Ifrd1 Regulates Osteoclast Differentiation through Enhancing the NF-κB/NFATc1 Pathway

Predicting and validating the pathway of Wnt3a-driven suppression of osteoclastogenesis

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