Constitutive Activation of β-Catenin in Differentiated Osteoclasts Induces Bone Loss in Mice

Sui, Xin; Deng, Shijian; Liu, Mengmeng; Fan, Linlin; Wang, Yunfei; Xu, Huaxing; Sun, Yao; Kishen, Anil; Zhang, Qi

doi:10.1159/000492549

Cited by 11 publications

(14 citation statements)

References 54 publications

(75 reference statements)

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“…While there is strong evidence supporting a role for OBdependent canonical Wnt signaling in the regulation of bone formation and bone resorption, the exact mechanisms by which this pathway affects bone mass via a cell-autonomous effect in OCs remain puzzling. Thus, in OCs, it has been shown that while canonical Wnt β-catenin cascade activation suppresses OCgenesis, noncanonical Wnt/Ror2/Jnk signaling activation favors it (23,(26)(27)(28)(29). Because Sfrp4 acts as a Wnt ligand decoy receptor, its function in skeletal homeostasis is related to regulation of distinct Wnt signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, Wei et al (26) have reported that while β-catenin activation favors OC proliferation of early precursor cells, its signal must be suppressed to have mature OCs. However, to complicate matters, it has been recently reported that expression of constitutively active β-catenin in OCs in vivo leads to increased OCgenesis (27). On the other hand, several pieces of evidence indicate that noncanonical Wnt signaling activation favors OCgenesis (28)(29)(30).…”

Section: Significancementioning

confidence: 99%

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Sfrp4 repression of the Ror2/Jnk cascade in osteoclasts protects cortical bone from excessive endosteal resorption

Chen

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Loss-of-function mutations in the Wnt inhibitor secreted frizzled receptor protein 4 (SFRP4) cause Pyle’s disease (OMIM 265900), a rare skeletal disorder characterized by wide metaphyses, significant thinning of cortical bone, and fragility fractures. In mice, we have shown that the cortical thinning seen in the absence ofSfrp4is associated with decreased periosteal and endosteal bone formation and increased endocortical resorption. While the increase in Rankl/Opg in cortical bone of mice lackingSfrp4suggests an osteoblast-dependent effect on endocortical osteoclast (OC) activity, whether Sfrp4 can cell-autonomously affect OCs is not known. We found thatSfrp4is expressed during bone marrow macrophage OC differentiation and that Sfrp4 significantly suppresses the ability of early and late OC precursors to respond to Rankl-induced OC differentiation.Sfrp4deletion in OCs resulted in activation of canonical Wnt/β-catenin and noncanonical Wnt/Ror2/Jnk signaling cascades. However, while inhibition of canonical Wnt/β-catenin signaling did not alter the effect ofSfrp4on OCgenesis, blocking the noncanonical Wnt/Ror2/Jnk cascade markedly suppressed its regulation of OC differentiation in vitro. Importantly, we report that deletion ofRor2exclusively in OCs (CtskCreRor2fl/fl) inSfrp4null mice significantly reversed the increased number of endosteal OCs seen in these mice and reduced their cortical thinning. Altogether, these data show autocrine and paracrine effects of Sfrp4 in regulating OCgenesis and demonstrate that the increase in endosteal OCs seen inSfrp4−/−mice is a consequence of noncanonical Wnt/Ror2/Jnk signaling activation in OCs overriding the negative effect that activation of canonical Wnt/β-catenin signaling has on OCgenesis.

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Section: Discussionmentioning

confidence: 99%

Section: Significancementioning

confidence: 99%

Sfrp4 repression of the Ror2/Jnk cascade in osteoclasts protects cortical bone from excessive endosteal resorption

Chen

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…The biphasic regulatory effect of the Wnt ligand Wnt3a on osteoclastogenesis is dependent on β-catenin. Wnt3a enhances the proliferation of osteoclast precursors through the activation of β-catenin and impairs the differentiation of osteoclast precursors due to β-catenin constitutive activation ( Sui et al, 2018 ). Besides, the stimulation of OPG in osteoblasts can also block osteoclastogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…Although current studies have also focused on the direct modulatory role of Wnt signaling in osteoclast differentiation, the results remain contradictory. Constitutively active β-catenin in osteoclast precursors barely forms osteoclasts, whereas the β-catenin signal is required for the proliferation of osteoclast precursors ( Sui et al, 2018 ). Furthermore, Wnt5a has been shown to activate the Ror2-JNK signaling and enhance RANKL-induced osteoclastogenesis ( Maeda et al, 2012 ).…”

Section: Introductionmentioning

confidence: 99%

Wnt7b Inhibits Osteoclastogenesis via AKT Activation and Glucose Metabolic Rewiring

et al. 2021

Front. Cell Dev. Biol.

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The imbalance between bone formation and bone resorption causes osteoporosis, which leads to severe bone fractures. It is known that increases in osteoclast numbers and activities are the main reasons for increasing bone resorption. Although extensive studies have investigated the regulation of osteoclastogenesis of bone marrow macrophages (BMMs), new pharmacological avenues still need to be unveiled for clinical purpose. Wnt ligands have been widely demonstrated as stimulators of bone formation; however, the inhibitory effect of the Wnt pathway in osteoclastogenesis is largely unknown. Here, we demonstrate that Wnt7b, a potent Wnt ligand that enhances bone formation and increases bone mass, also abolishes osteoclastogenesis in vitro. Importantly, enforced expression of Wnt in bone marrow macrophage lineage cells significantly disrupts osteoclast formation and activity, which leads to a dramatic increase in bone mass. Mechanistically, Wnt7b impacts the glucose metabolic process and AKT activation during osteoclastogenesis. Thus, we demonstrate that Wnt7b diminishes osteoclast formation, which will be beneficial for osteoporosis therapy in the future.

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“…It is reported that the reduction of Lrp5 in the early osteoclast lineage reduced trabecular bone mass, whereas its disruption in late osteoclast precursors did not alter the skeletal phenotype [ 22 ]. By contrast, the constitutive activation of β-catenin is reported to promote osteoclast formation, resulting in bone loss [ 23 ]. To the best of our knowledge, little is known about the role of Wnt-activated osteoclasts in the bone-tumor microenvironment.…”

Section: Introductionmentioning

confidence: 99%

Conversion of Osteoclasts into Bone-Protective, Tumor-Suppressing Cells

Sun

et al. 2021

Cancers

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Osteoclasts are a driver of a vicious bone-destructive cycle with breast cancer cells. Here, we examined whether this vicious cycle can be altered into a beneficial one by activating Wnt signaling with its activating agent, BML284. The conditioned medium, derived from Wnt-activated RAW264.7 pre-osteoclast cells (BM CM), reduced the proliferation, migration, and invasion of EO771 mammary tumor cells. The same inhibitory effect was obtained with BML284-treated primary human macrophages. In a mouse model, BM CM reduced the progression of mammary tumors and tumor-induced osteolysis and suppressed the tumor invasion to the lung. It also inhibited the differentiation of RANKL-stimulated osteoclasts and enhanced osteoblast differentiation. BM CM was enriched with atypical tumor-suppressing proteins such as Hsp90ab1 and enolase 1 (Eno1). Immunoprecipitation revealed that extracellular Hsp90ab1 interacted with latent TGFβ (LAP-TGFβ) as an inhibitor of TGFβ activation, while Hsp90ab1 and Eno1 interacted and suppressed tumor progression via CD44, a cell-adhesion receptor and a cancer stem cell marker. This study demonstrated that osteoclast-derived CM can be converted into a bone-protective, tumor-suppressing agent by activating Wnt signaling. The results shed a novel insight on the unexplored function of osteoclasts as a potential bone protector that may develop an unconventional strategy to combat bone metastasis.

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Constitutive Activation of β-Catenin in Differentiated Osteoclasts Induces Bone Loss in Mice

Cited by 11 publications

References 54 publications

Sfrp4 repression of the Ror2/Jnk cascade in osteoclasts protects cortical bone from excessive endosteal resorption

Sfrp4 repression of the Ror2/Jnk cascade in osteoclasts protects cortical bone from excessive endosteal resorption

Wnt7b Inhibits Osteoclastogenesis via AKT Activation and Glucose Metabolic Rewiring

Conversion of Osteoclasts into Bone-Protective, Tumor-Suppressing Cells

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