Continuous application of compressive force induces fusion of osteoclast-like RAW264.7 cells via upregulation of RANK and downregulation of LGR4

Matsuike, Rieko; Tanaka, Hideki; Nakai, Kumiko; Kanda, Mai; Nagasaki, Masao; Murakami, Fumiko; Shibata, Chika; Mayahara, Kotoe; Nakajima, Akira; Tanabe, Natsuko; Kawato, Takayuki; Maeno, Masao

doi:10.1016/j.lfs.2018.03.038

Cited by 16 publications

(20 citation statements)

References 34 publications

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“…Lgr4-deficient mice display delayed bone formation and reduced bone mass [106]. Moreover, mice carrying global or monocyte-specific knockout of Lgr4 exhibited robust activation of osteoclasts via RANKL signaling and bone loss [107], whereas Lgr4 was downregulated during in vitro osteoclast-like cells fusion [108]. These studies suggest the importance of Lgr4 in bone homeostasis.…”

Section: R-spondin Signaling and Tissue Homeostasismentioning

confidence: 96%

R-spondin signaling as a pivotal regulator of tissue development and homeostasis

Nagano

2019

Japanese Dental Science Review

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R-spondins (Rspos) are cysteine-rich secreted glycoproteins which control a variety of cellular functions and are essential for embryonic development and tissue homeostasis. R-spondins (Rspo1 to 4) have high structural similarity and share 60% sequence homology. It has been shown that their cysteine-rich furin-like (FU) domain and the thrombospondin (TSP) type I repeat domain are essential for initiating downstream signaling cascades and therefore for their biological functions. Although numerous studies have unveiled their pivotal role as critical developmental regulators, the most important finding is that Rspos synergize Wnt signaling. Recent studies have identified novel receptors for Rspos, the Lgr receptors, closely related orphans of the leucin-rich repeat containing G protein-coupled receptors, and proposed that Rspos potentiate canonical Wnt signaling via these receptors. Given that Wnt signaling is one of the most important developmental signaling pathways that controls cell fate decisions and tissue development, growth and homeostasis, Rspos may function as key players for these processes as well as potential therapeutic targets. Here, I recapitulate the Wnt signaling and then outline the biological role of Rspos in tissue development and homeostasis and explore the possibility that Rspos may be used as therapeutic targets.

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Section: R-spondin Signaling and Tissue Homeostasismentioning

confidence: 96%

R-spondin signaling as a pivotal regulator of tissue development and homeostasis

Nagano

2019

Japanese Dental Science Review

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“…It has been reported that compressive force can directly involve in osteoclastogenesis. Application of compressive force induced the differentiation of RAW264.7 cells into titrate‐resistant acid phosphatase (TRAP)‐positive multinuclear cells . Suture compression force can promote osteoclastogenesis leading to an increase in bone resorption and a decrease in bone density .…”

Section: Introductionmentioning

confidence: 99%

Compressive force‐induced autophagy in periodontal ligament cells downregulates osteoclastogenesis during tooth movement

Chen

Hua

2019

Journal of Periodontology

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Background Autophagy has recently emerged as a protective mechanism in response to compressive force and an important process in maintenance of bone homeostasis. It appears to be involved in the degradation of osteoclasts, osteoblasts, and osteocytes. The aim of this study was to investigate the role of compressive force‐induced autophagy in periodontal ligament (PDL) cells in regulating osteoclastogenesis of orthodontic tooth movement (OTM). Methods An OTM model and compressive force on PDL cells were employed to investigate the expression of autophagy markers in vivo and in vitro, respectively. Autophagosomes and autolysosomes were observed in PDL cells by transmission electron microscope (TEM) and autophagy LC3 double labelling. 3‐Methyladenine (3‐MA) and rapamycin were respectively used to inhibit and promote autophagy, and the effect of autophagy on osteoclastogenesis was explored via microcomputed tomography, hematoxylin and eosin (H&E) staining, histochemistry of titrate‐resistant acid phosphatase, and real‐time polymerase chain reaction (RT‐PCR) in vivo. Receptor activator of nuclear factor‐kappa B ligand/osteoprotegerin (RANKL/OPG) was investigated by RT‐PCR and ELISA in vitro. Results Orthodontic force‐induced autophagy was prominent on the pressured side of PDL tissues. Administration of 3‐MA downregulated bone density and upregulated osteoclasts, while rapamycin had reverse results in OTM. The autophagy activity increased initially then decreased in PDL cells during compressive force application and responded to light force. In PDL cells, administration of 3‐MA upregulated while rapamycin downregulated the RANKL/OPG ratio. Conclusion Autophagy is activated by compressive force in PDL cells. Besides, it could modulate OTM by negatively regulating osteoclastogenesis and keep bone homeostasis via RANKL/OPG signaling.

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“…In orthodontic treatments, continuous mechanical force induces alveolar bone remodeling within the physiological range during orthodontic tooth movement [6]. Recently, we investigated the effects of compressive force on osteoclastogenesis in vitro using the RAW264.7 mouse monocyte/macrophage lineage; cells were continuously exposed to compressive force created by increasing the amount of the culture solution (over 4 days) for RANKL-induced osteoclast differentiation [16]. Continuous stimulation with compressive force induced the fusion of cells by the upregulation of the two cell fusion factors described above via RANK-RANKL signaling.…”

Section: Introductionmentioning

confidence: 99%

“…Continuous stimulation with compressive force induced the fusion of cells by the upregulation of the two cell fusion factors described above via RANK-RANKL signaling. As a result, multinucleated cells positive for tartrate-resistant acid phosphatase (TRAP), a marker of mature osteoclasts, increased depending on the magnitude of the compressive force that was exerted on the cells [16]. To the best of our knowledge, this is the first report of the continuous effects of the direct stimulation of osteoclast precursor cells by compressive force on osteoclastogenesis.…”

Section: Introductionmentioning

confidence: 99%

Continuous Compressive Force Induces Differentiation of Osteoclasts with High Levels of Inorganic Dissolution

et al. 2019

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Background Osteoclast precursor cells are constitutively differentiated into mature osteoclasts on bone tissues. We previously reported that the continuous stimulation of RAW264.7 precursor cells with compressive force induces the formation of multinucleated giant cells via receptor activator of nuclear factor κB (RANK)-RANK ligand (RANKL) signaling. Here, we examined the bone resorptive function of multinucleated osteoclasts induced by continuous compressive force. Material/Methods Cells were continuously stimulated with 0.3, 0.6, and 1.1 g/cm 2 compressive force created by increasing the amount of the culture solution in the presence of RANKL. Actin ring organization was evaluated by fluorescence microscopy. mRNA expression of genes encoding osteoclastic bone resorption-related enzymes was examined by quantitative real-time reverse transcription-polymerase chain reaction. Mineral resorption was evaluated using calcium phosphate-coated plates. Results Multinucleated osteoclast-like cells with actin rings were observed for all three magnitudes of compressive force, and the area of actin rings increased as a function of the applied force. Carbonic anhydrase II expression as well as calcium elution from the calcium phosphate plate was markedly higher after stimulation with 0.6 and 1.1 g/cm 2 force than 0.3 g/cm 2 . Matrix metalloproteinase-9 expression decreased and cathepsin K expression increased slightly by the continuous application of compressive force. Conclusions Our study demonstrated that multinucleated osteoclast-like cells induced by the stimulation of RAW264.7 cells with continuous compressive force exhibit high dissolution of the inorganic phase of bone by upregulating carbonic anhydrase II expression and actin ring formation. These findings improve our understanding of the role of mechanical load in bone remodeling.

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Continuous application of compressive force induces fusion of osteoclast-like RAW264.7 cells via upregulation of RANK and downregulation of LGR4

Cited by 16 publications

References 34 publications

R-spondin signaling as a pivotal regulator of tissue development and homeostasis

R-spondin signaling as a pivotal regulator of tissue development and homeostasis

Compressive force‐induced autophagy in periodontal ligament cells downregulates osteoclastogenesis during tooth movement

Continuous Compressive Force Induces Differentiation of Osteoclasts with High Levels of Inorganic Dissolution

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